VCV000045487.20 - ClinVar

NM_006393.3(NEBL):c.1861A>G (p.Ile621Val)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Benign/Likely benign
Benign (4); Likely benign (1)

5 out of 7 submissions contributed to this classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Functional data are available for this variant

Variant Details

Identifiers

NM_006393.3(NEBL):c.1861A>G (p.Ile621Val)

Variation ID: 45487 Accession: VCV000045487.20

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 10p12.31 10: 20826455 (GRCh38) [ NCBI UCSC ] 10: 21115384 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	May 29, 2016	Feb 15, 2026	Jan 26, 2026

HGVS

Nucleotide	Protein	Molecular consequence
NM_006393.3:c.1861A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_006384.1:p.Ile621Val	missense
NM_001173484.2:c.358-13515A>G		intron variant
NM_001377322.1:c.358-13515A>G		intron variant
NM_001377323.1:c.310-13515A>G		intron variant
NM_001377324.1:c.301-13515A>G		intron variant
NM_001377325.1:c.292-13515A>G		intron variant
NM_001377326.1:c.250-13515A>G		intron variant
NM_001377327.1:c.250-13515A>G		intron variant
NM_001377328.1:c.250-13515A>G		intron variant
NM_213569.2:c.358-13515A>G		intron variant
NC_000010.11:g.20826455T>C
NC_000010.10:g.21115384T>C
NG_017092.1:g.352733A>G
LRG_411:g.352733A>G
LRG_411t1:c.358-13515A>G
LRG_411t2:c.1861A>G	LRG_411p2:p.Ile621Val

... more HGVS ... less HGVS

Protein change

I621V

Other names

p.I621V:ATT>GTT

Canonical SPDI

NC_000010.11:20826454:T:C

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00459 (C)

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00043

The Genome Aggregation Database (gnomAD), exomes 0.00124

Exome Aggregation Consortium (ExAC) 0.00149

1000 Genomes Project 30x 0.00453

1000 Genomes Project 0.00459

The Genome Aggregation Database (gnomAD) 0.00500

Trans-Omics for Precision Medicine (TOPMed) 0.00531

The Genome Aggregation Database (gnomAD) 0.00532

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00577

Links

ClinGen: CA136414 dbSNP: rs79718972 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
NEBL		No evidence available	No evidence available	GRCh38 GRCh37	1445	1512

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not specified	Benign/Likely benign (3)	criteria provided, multiple submitters, no conflicts	Apr 26, 2023	RCV000038692.7
Primary dilated cardiomyopathy	Benign (1)	criteria provided, single submitter	Jan 26, 2026	RCV000463893.13
NEBL-related disorder	Benign (1)	no assertion criteria provided	Feb 21, 2019	RCV003964860.2
not provided	Benign (1)	criteria provided, single submitter	-	RCV004717923.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	Expand all rows Collapse all rows Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Benign (Apr 28, 2014) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification (06012015))	not specified	GeneDx Accession: SCV000170737.11 First in ClinVar: Jun 23, 2014 Last updated: May 29, 2016	Comment: show This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Benign (Mar 19, 2012) C Contributing to aggregate classification	criteria provided, single submitter (LMM Criteria)	not specified	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000062370.6 First in ClinVar: May 03, 2013 Last updated: May 29, 2016	Comment: show p.Ile621Val in Exon 18 of NEBL: This variant is not expected to have clinical si gnificance because it has been identified in 1.8% (66/3738) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs79718972). (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: not provided more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: not provided Number of individuals with the variant: 8

Likely benign (Apr 26, 2023) C Contributing to aggregate classification	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	not specified	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV003928278.1 First in ClinVar: Jun 03, 2023 Last updated: Jun 03, 2023	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Benign (-) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not provided (Unknown mechanism)	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005320516.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024	Observation: 1 Collection method: not provided Allele origin: germline Affected status: yes Observation 1 Collection method: not provided Allele origin: germline Affected status: yes

Benign (Jan 26, 2026) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Primary dilated cardiomyopathy	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000563544.10 First in ClinVar: Apr 17, 2017 Last updated: Feb 15, 2026	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Benign (Feb 21, 2019) N Not contributing to aggregate classification	no assertion criteria provided	NEBL-related condition	PreventionGenetics, part of Exact Sciences Accession: SCV004779917.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: show This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Comment:

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Comment:

p.Ile621Val in Exon 18 of NEBL: This variant is not expected to have clinical si gnificance because it has been identified in 1.8% (66/3738) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs79718972).

Citations for germline classification of this variant

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Submissions - Functional Data

functionally abnormal -- skipped exon, retained intron

assessed by RNAseq

Result:

junction spanning - exon skipping (p=0.0),junction spanning - intron inclusion (p=0.0288),read abundance - intron inclusion (p=0.0204)

Modifies an exonic cryptic donor site at NC_000010.10:g.21115384 from -15.47 to 3.16 bits. Significant p-values: junction spanning - exon skipping (1 reads, p=0.0), junction spanning - intron inclusion (1 reads, p=0.0288), read abundance - intron inclusion (168 reads, p=0.0204). Computations were originally performed using genomic coordinates. This variant was mapped to an appropriate current MANE database designation or, if not present in this source, to the longest relevant transcript in the Biocommons Universal Transcript Archive using the hgvs Python package. The original genomic coordinate was based on GRCh37 and was submitted as an "Alternate designation". Modifications of Figure 2 of PMID:31275557 for ClinVar: a) "strongly corroborating Veridical p-value" refers to "junction-spanning" evidence types; b) add the text "and natural site < 300 nucleotides away?" to "Ri,final > nearest natural site Ri"; c) "Aberrant" and "Likely aberrant" classifications are now both defined as "Functionally abnormal" (analogous to ACMG/AMP reporting); d) "Allele-specific alternative splicing" classification now defined as "Function uncertain" (based on results for similar variants in PMID: 32211018); e) average heterozygosity based-criteria no longer contribute to classification.

Citation: PubMed: 31275557

Dr. Peter K. Rogan Lab, Western University

Accession: SCV006755296.1

Submitted: 2025-10-17

Assay description:

In the sample (TCGA-DO-A1JZ), the counts of splice junction spanning reads and abundance of the transcript adjacent to this mutation were compared with RNASeq data from matched tissues and tumors lacking the same mutation using Veridical (PMID:24741438)

Disease context: Thyroid cancer, nonmedullary, 1
Transcript, protein change: NM_006393.3:c.1861A>G, I621V
Molecular phenotype measured: splicing
Cell line: TCGA-DO-A1JZ
Tissue: Thyroid Carcinoma (THCA)
Collection method: in vitro
Species: human
Number of controls: 533

Text-mined citations for rs79718972 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Feb 15, 2026