rs649568

Variant names:

• chr11-113237017-G-A
• rs649568
• NM_181351.5:c.1825+1853G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_181351.5(NCAM1):​c.1825+1853G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0474 in 152,262 control chromosomes in the GnomAD database, including 285 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 0.047 (285 hom., cov: 33)
• Consequence: NCAM1 NM_181351.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.326
• Publications: 3 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.152 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181351.5. 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.1825+1853G>A		intron	N/A	NP_851996.2	P13591-2
	NCAM1	NM_001400624.1		c.1825+1853G>A		intron	N/A	NP_001387553.1
	NCAM1	NM_001400620.1		c.1810+702G>A		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.1825+1853G>A		intron	N/A	ENSP00000318472.8	P13591-2
	NCAM1	ENST00000533073.5	TSL:1	c.322+1853G>A		intron	N/A	ENSP00000486406.1	A0A0D9SF98
	NCAM1	ENST00000619839.4	TSL:5	c.1903+1853G>A		intron	N/A	ENSP00000480132.1	A0A087WWD4

Frequencies

GnomAD3 genomes AF: 0.0475 AC: 7222 AN: 152144 Hom.: 286 Cov.: 33

Gnomad AFR AF: 0.0894

Gnomad AMI AF: 0.0275

Gnomad AMR AF: 0.0301

Gnomad ASJ AF: 0.0328

Gnomad EAS AF: 0.160

Gnomad SAS AF: 0.0307

Gnomad FIN AF: 0.0107

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0254

Gnomad OTH AF: 0.0382

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0474 AC: 7224 AN: 152262 Hom.: 285 Cov.: 33 AF XY: 0.0473 AC XY: 3524 AN XY: 74448

African (AFR) AF: 0.0892 AC: 3706 AN: 41548

American (AMR) AF: 0.0302 AC: 462 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0328 AC: 114 AN: 3472

East Asian (EAS) AF: 0.161 AC: 831 AN: 5174

South Asian (SAS) AF: 0.0305 AC: 147 AN: 4818

European-Finnish (FIN) AF: 0.0107 AC: 113 AN: 10608

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0254 AC: 1728 AN: 68020

Other (OTH) AF: 0.0383 AC: 81 AN: 2116

Alfa AF: 0.0370 Hom.: 314

Bravo AF: 0.0510

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.7
DANN	Benign	0.43
PhyloP100		-0.33
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: rs649568; hg19: chr11-113107739; COSMIC: COSV57518176; COSMIC: COSV57518176;