Genetic Variant ENST00000637974.1:c.2522-5121T>C (chr11-119308297-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000637974.1(CBL):c.2522-5121T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.576 in 153,534 control chromosomes in the GnomAD database, including 27,800 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.58 ( 27593 hom., cov: 31)

Exomes 𝑓: 0.49 ( 207 hom. )

Consequence

CBL
ENST00000637974.1 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -4.92

Publications

6 publications found

Variant links:

Genes affected

CBL (HGNC:1541): (Cbl proto-oncogene) This gene is a proto-oncogene that encodes a RING finger E3 ubiquitin ligase. The encoded protein is one of the enzymes required for targeting substrates for degradation by the proteasome. This protein mediates the transfer of ubiquitin from ubiquitin conjugating enzymes (E2) to specific substrates. This protein also contains an N-terminal phosphotyrosine binding domain that allows it to interact with numerous tyrosine-phosphorylated substrates and target them for proteasome degradation. As such it functions as a negative regulator of many signal transduction pathways. This gene has been found to be mutated or translocated in many cancers including acute myeloid leukaemia, and expansion of CGG repeats in the 5' UTR has been associated with Jacobsen syndrome. Mutations in this gene are also the cause of Noonan syndrome-like disorder. [provided by RefSeq, Jul 2016]

CBL links:

MCAM (HGNC:6934): (melanoma cell adhesion molecule) Involved in glomerular filtration and vascular wound healing. Acts upstream of or within angiogenesis. Located in external side of plasma membrane. Biomarker of chronic obstructive pulmonary disease and uveal melanoma. [provided by Alliance of Genome Resources, Apr 2022]

MCAM links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.825 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBL	NM_005188.4 link	c.*8516T>C		downstream_gene_variant		ENST00000264033.6	NP_005179.2
MCAM	NM_006500.3 link	c.*1589A>G		downstream_gene_variant		ENST00000264036.6	NP_006491.2	P43121-1A0A024R3I5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBL	ENST00000264033.6 link	c.*8516T>C		downstream_gene_variant		1	NM_005188.4	ENSP00000264033.3		P22681
MCAM	ENST00000264036.6 link	c.*1589A>G		downstream_gene_variant		1	NM_006500.3	ENSP00000264036.4		P43121-1

Frequencies

GnomAD3 genomes

AF:

0.577

AC:

87610

AN:

151868

Hom.:

27564

Cov.:

show subpopulations

Gnomad AFR

AF:

0.833

Gnomad AMI

AF:

0.474

Gnomad AMR

AF:

0.451

Gnomad ASJ

AF:

0.589

Gnomad EAS

AF:

0.726

Gnomad SAS

AF:

0.657

Gnomad FIN

AF:

0.431

Gnomad MID

AF:

0.551

Gnomad NFE

AF:

0.456

Gnomad OTH

AF:

0.569

GnomAD4 exome

AF:

0.491

AC:

760

AN:

1548

Hom.:

207

AF XY:

0.504

AC XY:

367

AN XY:

728

show subpopulations

African (AFR)

AF:

0.917

AC:

AN:

American (AMR)

AF:

0.500

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.531

AC:

AN:

East Asian (EAS)

AF:

0.738

AC:

152

AN:

206

South Asian (SAS)

AF:

0.600

AC:

AN:

European-Finnish (FIN)

AF:

0.353

AC:

AN:

184

Middle Eastern (MID)

AF:

0.667

AC:

AN:

European-Non Finnish (NFE)

AF:

0.440

AC:

383

AN:

870

Other (OTH)

AF:

0.509

AC:

AN:

112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.577

AC:

87691

AN:

151986

Hom.:

27593

Cov.:

AF XY:

0.579

AC XY:

43002

AN XY:

74282

show subpopulations

African (AFR)

AF:

0.832

AC:

34516

AN:

41468

American (AMR)

AF:

0.450

AC:

6878

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.589

AC:

2044

AN:

3468

East Asian (EAS)

AF:

0.726

AC:

3734

AN:

5144

South Asian (SAS)

AF:

0.656

AC:

3163

AN:

4822

European-Finnish (FIN)

AF:

0.431

AC:

4544

AN:

10532

Middle Eastern (MID)

AF:

0.548

AC:

161

AN:

294

European-Non Finnish (NFE)

AF:

0.456

AC:

31009

AN:

67954

Other (OTH)

AF:

0.573

AC:

1210

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1687

3375

5062

6750

8437

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

720

1440

2160

2880

3600

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.497

Hom.:

21548

Bravo

AF:

0.588

Asia WGS

AF:

0.677

AC:

2352

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.034

(source)

DANN

Benign

0.57

PhyloP100

-4.9

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over