11-113207325-C-T

Position:

• chr11-113207325-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_181351.5(NCAM1):​c.693C>T​(p.Val231=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0144 in 1,614,026 control chromosomes in the GnomAD database, including 204 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0098 (8 hom., cov: 32)
  • Exomes 𝑓: 0.015 (196 hom.)
• Consequence: NCAM1 NM_181351.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.117

Genes affected

NCAM1 (HGNC:7656): (neural cell adhesion molecule 1) This gene encodes a cell adhesion protein which is a member of the immunoglobulin superfamily. The encoded protein is involved in cell-to-cell interactions as well as cell-matrix interactions during development and differentiation. The encoded protein plays a role in the development of the nervous system by regulating neurogenesis, neurite outgrowth, and cell migration. This protein is also involved in the expansion of T lymphocytes, B lymphocytes and natural killer (NK) cells which play an important role in immune surveillance. This protein plays a role in signal transduction by interacting with fibroblast growth factor receptors, N-cadherin and other components of the extracellular matrix and by triggering signalling cascades involving FYN-focal adhesion kinase (FAK), mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3-kinase (PI3K). One prominent isoform of this gene, cell surface molecule CD56, plays a role in several myeloproliferative disorders such as acute myeloid leukemia and differential expression of this gene is associated with differential disease progression. For example, increased expression of CD56 is correlated with lower survival in acute myeloid leukemia patients whereas increased severity of COVID-19 is correlated with decreased abundance of CD56-expressing NK cells in peripheral blood. Alternative splicing results in multiple transcript variants encoding distinct protein isoforms. [provided by RefSeq, Aug 2020]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 11-113207325-C-T is Benign according to our data. Variant chr11-113207325-C-T is described in ClinVar as [Benign]. Clinvar id is 770406.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.117 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00975 (1486/152360) while in subpopulation NFE AF= 0.0159 (1083/68032). AF 95% confidence interval is 0.0151. There are 8 homozygotes in gnomad4. There are 700 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1486 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NCAM1	NM_181351.5	c.693C>T	p.Val231=	synonymous_variant	6/20	ENST00000316851.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NCAM1	ENST00000316851.12	c.693C>T	p.Val231=	synonymous_variant	6/20	5	NM_181351.5	P3

Frequencies

GnomAD3 genomes AF: 0.00975 AC: 1485 AN: 152242 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00273

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0101

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00704

Gnomad FIN AF: 0.00367

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0159

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.00979 AC: 2441 AN: 249266 Hom.: 21 AF XY: 0.0102 AC XY: 1373 AN XY: 135232

Gnomad AFR exome AF: 0.00316

Gnomad AMR exome AF: 0.00744

Gnomad ASJ exome AF: 0.00735

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00533

Gnomad FIN exome AF: 0.00450

Gnomad NFE exome AF: 0.0152

Gnomad OTH exome AF: 0.0140

GnomAD4 exome AF: 0.0149 AC: 21710 AN: 1461666 Hom.: 196 Cov.: 31 AF XY: 0.0145 AC XY: 10561 AN XY: 727114

Gnomad4 AFR exome AF: 0.00254

Gnomad4 AMR exome AF: 0.00780

Gnomad4 ASJ exome AF: 0.00635

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00581

Gnomad4 FIN exome AF: 0.00442

Gnomad4 NFE exome AF: 0.0176

Gnomad4 OTH exome AF: 0.0132

GnomAD4 genome AF: 0.00975 AC: 1486 AN: 152360 Hom.: 8 Cov.: 32 AF XY: 0.00939 AC XY: 700 AN XY: 74518

Gnomad4 AFR AF: 0.00272

Gnomad4 AMR AF: 0.0101

Gnomad4 ASJ AF: 0.00778

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00725

Gnomad4 FIN AF: 0.00367

Gnomad4 NFE AF: 0.0159

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.0129 Hom.: 3

Bravo AF: 0.0102

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.0166

EpiControl AF: 0.0161

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 11, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	8.2
DANN	Benign	0.69

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

Publications

LitVar

Other links and lift over

dbSNP: rs17115156; hg19: chr11-113078047; COSMIC: COSV57510452; COSMIC: COSV57510452;