NM_005188.4(CBL):c.1228-10dup AND not specified

Clinical significance:Benign/Likely benign (Last evaluated: Oct 22, 2019)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000038349.3

Allele description [Variation Report for NM_005188.4(CBL):c.1228-10dup]

NM_005188.4(CBL):c.1228-10dup

Gene:
CBL:Cbl proto-oncogene [Gene - OMIM - HGNC]
Variant type:
Duplication
Cytogenetic location:
11q23.3
Genomic location:
Preferred name:
NM_005188.4(CBL):c.1228-10dup
HGVS:
  • NC_000011.10:g.119278500dup
  • NG_016808.1:g.77221dup
  • NM_005188.4:c.1228-10dupMANE SELECT
  • LRG_608t1:c.1228-10dup
  • LRG_608:g.77221dup
  • NC_000011.9:g.119149208_119149209insT
  • NC_000011.9:g.119149210dup
  • NM_005188.2:c.1228-10_1228-9insT
  • NM_005188.3:c.1228-10dup
  • NM_005188.3:c.1228-10dupT
  • c.1228-10_1228-9insT
Links:
dbSNP: rs397517078
NCBI 1000 Genomes Browser:
rs397517078
Observations:
2

Condition(s)

Synonyms:
AllHighlyPenetrant
Identifiers:
MedGen: CN169374

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000062021Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicinecriteria provided, single submitter
Likely benign
(Jun 14, 2012)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001362307Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Benign
(Oct 22, 2019)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot provided22not providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]
PMID:
24033266
PMCID:
PMC3995020

Myeloid leukemia development in c-Cbl RING finger mutant mice is dependent on FLT3 signaling.

Rathinam C, Thien CB, Flavell RA, Langdon WY.

Cancer Cell. 2010 Oct 19;18(4):341-52. doi: 10.1016/j.ccr.2010.09.008.

PubMed [citation]
PMID:
20951944
See all PubMed Citations (5)

Details of each submission

From Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, SCV000062021.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided2not providednot providedclinical testing PubMed (1)

Description

1228-10_1228-9insT in intron 8 of CBL: This variant is not expected to have clin ical significance because it is not located within the splice consensus sequence .

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided2not provided2not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001362307.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

Variant summary: CBL c.1228-10dupT alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00095 in 251332 control chromosomes, predominantly at a frequency of 0.008 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 3200 fold of the estimated maximal expected allele frequency for a pathogenic variant in CBL causing Noonan Syndrome and Related Conditions phenotype (2.5e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. To our knowledge, no occurrence of c.1228-10dupT in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrence with a pathogenic variant has been reported (NF1 c.2540T>C, p.L847P), providing supporting evidence for a benign role. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jul 7, 2021

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