rs635596

Variant names:

• chr11-113242793-G-A
• rs635596
• NM_181351.5:c.1826-3575G>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.1826-3575G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.835 in 1,611,638 control chromosomes in the GnomAD database, including 562,701 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 0.81 (49954 hom., cov: 32)
  • Exomes 𝑓: 0.84 (512747 hom.)
• Consequence: NCAM1 NM_181351.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.29
• Publications: 12 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=-0.61).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.882 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NCAM1	NM_181351.5	c.1826-3575G>A		intron_variant	Intron 14 of 19	ENST00000316851.12	NP_851996.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NCAM1	ENST00000316851.12	c.1826-3575G>A		intron_variant	Intron 14 of 19	5	NM_181351.5	ENSP00000318472.8

Frequencies

GnomAD3 genomes AF: 0.809 AC: 122961 AN: 151962 Hom.: 49925 Cov.: 32

Gnomad AFR AF: 0.744

Gnomad AMI AF: 0.977

Gnomad AMR AF: 0.813

Gnomad ASJ AF: 0.872

Gnomad EAS AF: 0.843

Gnomad SAS AF: 0.904

Gnomad FIN AF: 0.796

Gnomad MID AF: 0.880

Gnomad NFE AF: 0.834

Gnomad OTH AF: 0.824

GnomAD2 exomes AF: 0.838 AC: 208835 AN: 249234 AF XY: 0.844

Gnomad AFR exome AF: 0.737

Gnomad AMR exome AF: 0.849

Gnomad ASJ exome AF: 0.872

Gnomad EAS exome AF: 0.832

Gnomad FIN exome AF: 0.799

Gnomad NFE exome AF: 0.835

Gnomad OTH exome AF: 0.831

GnomAD4 exome AF: 0.837 AC: 1222377 AN: 1459558 Hom.: 512747 Cov.: 42 AF XY: 0.840 AC XY: 609969 AN XY: 726190

African (AFR) AF: 0.742 AC: 24808 AN: 33430

American (AMR) AF: 0.843 AC: 37713 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.870 AC: 22731 AN: 26118

East Asian (EAS) AF: 0.853 AC: 33864 AN: 39680

South Asian (SAS) AF: 0.912 AC: 78670 AN: 86216

European-Finnish (FIN) AF: 0.802 AC: 42763 AN: 53328

Middle Eastern (MID) AF: 0.868 AC: 4999 AN: 5760

European-Non Finnish (NFE) AF: 0.834 AC: 926246 AN: 1109994

Other (OTH) AF: 0.839 AC: 50583 AN: 60316

GnomAD4 genome AF: 0.809 AC: 123042 AN: 152080 Hom.: 49954 Cov.: 32 AF XY: 0.807 AC XY: 59991 AN XY: 74338

African (AFR) AF: 0.745 AC: 30866 AN: 41450

American (AMR) AF: 0.812 AC: 12423 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.872 AC: 3025 AN: 3470

East Asian (EAS) AF: 0.843 AC: 4359 AN: 5170

South Asian (SAS) AF: 0.904 AC: 4352 AN: 4814

European-Finnish (FIN) AF: 0.796 AC: 8409 AN: 10566

Middle Eastern (MID) AF: 0.874 AC: 257 AN: 294

European-Non Finnish (NFE) AF: 0.834 AC: 56724 AN: 68000

Other (OTH) AF: 0.822 AC: 1736 AN: 2112

Alfa AF: 0.825 Hom.: 10689

Bravo AF: 0.807

Asia WGS AF: 0.843 AC: 2929 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	3.4
DANN	Benign	0.70
PhyloP100		-1.3
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: rs635596; hg19: chr11-113113515;