11-113240779-T-C

Variant names:

• chr11-113240779-T-C
• rs2303377
• NM_181351.5:c.1826-5589T>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_001400621.1(NCAM1):​c.1841-7T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.399 in 1,610,692 control chromosomes in the GnomAD database, including 133,042 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.37 (11181 hom., cov: 32)
  • Exomes 𝑓: 0.40 (121861 hom.)
• Consequence: NCAM1 NM_001400621.1 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.13
• Publications: 21 publications found

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

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.566 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001400621.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCAM1	NM_181351.5	MANE Select	c.1826-5589T>C		intron	N/A	NP_851996.2	P13591-2
	NCAM1	NM_001400624.1		c.1825+5615T>C		intron	N/A	NP_001387553.1
	NCAM1	NM_001400620.1		c.1810+4464T>C		intron	N/A	NP_001387549.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCAM1	ENST00000316851.12	TSL:5 MANE Select	c.1826-5589T>C		intron	N/A	ENSP00000318472.8	P13591-2
	NCAM1	ENST00000533073.5	TSL:1	c.322+5615T>C		intron	N/A	ENSP00000486406.1	A0A0D9SF98
	NCAM1	ENST00000619839.4	TSL:5	c.1904-5589T>C		intron	N/A	ENSP00000480132.1	A0A087WWD4

Frequencies

GnomAD3 genomes AF: 0.367 AC: 55781 AN: 151870 Hom.: 11181 Cov.: 32

Gnomad AFR AF: 0.223

Gnomad AMI AF: 0.308

Gnomad AMR AF: 0.433

Gnomad ASJ AF: 0.415

Gnomad EAS AF: 0.584

Gnomad SAS AF: 0.501

Gnomad FIN AF: 0.543

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.386

Gnomad OTH AF: 0.362

GnomAD2 exomes AF: 0.438 AC: 109079 AN: 249182 AF XY: 0.437

Gnomad AFR exome AF: 0.211

Gnomad AMR exome AF: 0.543

Gnomad ASJ exome AF: 0.404

Gnomad EAS exome AF: 0.569

Gnomad FIN exome AF: 0.534

Gnomad NFE exome AF: 0.387

Gnomad OTH exome AF: 0.401

GnomAD4 exome AF: 0.402 AC: 586063 AN: 1458704 Hom.: 121861 Cov.: 34 AF XY: 0.405 AC XY: 293838 AN XY: 725790

African (AFR) AF: 0.216 AC: 7240 AN: 33446

American (AMR) AF: 0.525 AC: 23478 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.405 AC: 10582 AN: 26122

East Asian (EAS) AF: 0.613 AC: 24320 AN: 39678

South Asian (SAS) AF: 0.493 AC: 42505 AN: 86160

European-Finnish (FIN) AF: 0.526 AC: 28084 AN: 53370

Middle Eastern (MID) AF: 0.354 AC: 2044 AN: 5766

European-Non Finnish (NFE) AF: 0.383 AC: 424265 AN: 1109182

Other (OTH) AF: 0.391 AC: 23545 AN: 60264

GnomAD4 genome AF: 0.367 AC: 55808 AN: 151988 Hom.: 11181 Cov.: 32 AF XY: 0.379 AC XY: 28178 AN XY: 74252

African (AFR) AF: 0.223 AC: 9259 AN: 41482

American (AMR) AF: 0.434 AC: 6625 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.415 AC: 1440 AN: 3470

East Asian (EAS) AF: 0.584 AC: 3011 AN: 5160

South Asian (SAS) AF: 0.500 AC: 2408 AN: 4814

European-Finnish (FIN) AF: 0.543 AC: 5706 AN: 10516

Middle Eastern (MID) AF: 0.320 AC: 94 AN: 294

European-Non Finnish (NFE) AF: 0.386 AC: 26225 AN: 67950

Other (OTH) AF: 0.360 AC: 760 AN: 2110

Alfa AF: 0.369 Hom.: 25097

Bravo AF: 0.353

Asia WGS AF: 0.520 AC: 1806 AN: 3478

EpiCase AF: 0.375

EpiControl AF: 0.381

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	19
DANN	Benign	0.89
PhyloP100		1.1
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: rs2303377; hg19: chr11-113111501; COSMIC: COSV57509711;