11-119310460-T-C

Variant names:

• chr11-119310460-T-C
• rs2249466
• NM_006500.3:c.1800A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_006500.3(MCAM):​c.1800A>G​(p.Leu600Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.723 in 1,601,838 control chromosomes in the GnomAD database, including 420,927 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 0.73 (40376 hom., cov: 32)
  • Exomes 𝑓: 0.72 (380551 hom.)
• Consequence: MCAM NM_006500.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.86
• Publications: 40 publications found

Genes affected

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]

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 Gene-Disease associations (from GenCC):

• CBL-related disorder

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia, Genomics England PanelApp
• juvenile myelomonocytic leukemia

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Noonan syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP7: Synonymous conserved (PhyloP=1.86 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.798 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCAM	NM_006500.3	c.1800A>G	p.Leu600Leu	synonymous_variant	Exon 15 of 16	ENST00000264036.6	NP_006491.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCAM	ENST00000264036.6	c.1800A>G	p.Leu600Leu	synonymous_variant	Exon 15 of 16	1	NM_006500.3	ENSP00000264036.4

Frequencies

GnomAD3 genomes AF: 0.727 AC: 110524 AN: 151980 Hom.: 40330 Cov.: 32

Gnomad AFR AF: 0.742

Gnomad AMI AF: 0.725

Gnomad AMR AF: 0.784

Gnomad ASJ AF: 0.643

Gnomad EAS AF: 0.627

Gnomad SAS AF: 0.819

Gnomad FIN AF: 0.704

Gnomad MID AF: 0.715

Gnomad NFE AF: 0.715

Gnomad OTH AF: 0.717

GnomAD2 exomes AF: 0.742 AC: 186307 AN: 251222 AF XY: 0.742

Gnomad AFR exome AF: 0.746

Gnomad AMR exome AF: 0.849

Gnomad ASJ exome AF: 0.629

Gnomad EAS exome AF: 0.644

Gnomad FIN exome AF: 0.710

Gnomad NFE exome AF: 0.718

Gnomad OTH exome AF: 0.721

GnomAD4 exome AF: 0.723 AC: 1048251 AN: 1449740 Hom.: 380551 Cov.: 32 AF XY: 0.725 AC XY: 523679 AN XY: 721948

African (AFR) AF: 0.747 AC: 24813 AN: 33216

American (AMR) AF: 0.841 AC: 37607 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.626 AC: 16332 AN: 26076

East Asian (EAS) AF: 0.654 AC: 25937 AN: 39640

South Asian (SAS) AF: 0.820 AC: 70563 AN: 86032

European-Finnish (FIN) AF: 0.710 AC: 37765 AN: 53206

Middle Eastern (MID) AF: 0.718 AC: 4117 AN: 5736

European-Non Finnish (NFE) AF: 0.716 AC: 788121 AN: 1101122

Other (OTH) AF: 0.717 AC: 42996 AN: 59990

GnomAD4 genome AF: 0.727 AC: 110628 AN: 152098 Hom.: 40376 Cov.: 32 AF XY: 0.729 AC XY: 54206 AN XY: 74326

African (AFR) AF: 0.743 AC: 30825 AN: 41500

American (AMR) AF: 0.784 AC: 11997 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.643 AC: 2232 AN: 3470

East Asian (EAS) AF: 0.627 AC: 3235 AN: 5162

South Asian (SAS) AF: 0.819 AC: 3947 AN: 4820

European-Finnish (FIN) AF: 0.704 AC: 7438 AN: 10558

Middle Eastern (MID) AF: 0.721 AC: 212 AN: 294

European-Non Finnish (NFE) AF: 0.715 AC: 48568 AN: 67970

Other (OTH) AF: 0.716 AC: 1513 AN: 2114

Alfa AF: 0.721 Hom.: 76367

Bravo AF: 0.732

Asia WGS AF: 0.737 AC: 2559 AN: 3478

EpiCase AF: 0.706

EpiControl AF: 0.713

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	12
DANN	Benign	0.85
PhyloP100		1.9
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs2249466; hg19: chr11-119181170; COSMIC: COSV50654043; COSMIC: COSV50654043;