11-113235185-C-A

Variant names:

• chr11-113235185-C-A
• rs646558
• NM_181351.5:c.1825+21C>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+21C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.225 in 1,613,474 control chromosomes in the GnomAD database, including 44,872 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 0.28 (7443 hom., cov: 33)
  • Exomes 𝑓: 0.22 (37429 hom.)
• Consequence: NCAM1 NM_181351.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0490
• Publications: 16 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=-0.81).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.484 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NCAM1	NM_181351.5	c.1825+21C>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.1825+21C>A		intron_variant	Intron 14 of 19	5	NM_181351.5	ENSP00000318472.8

Frequencies

GnomAD3 genomes AF: 0.284 AC: 43179 AN: 152046 Hom.: 7420 Cov.: 33

Gnomad AFR AF: 0.489

Gnomad AMI AF: 0.155

Gnomad AMR AF: 0.233

Gnomad ASJ AF: 0.146

Gnomad EAS AF: 0.243

Gnomad SAS AF: 0.125

Gnomad FIN AF: 0.195

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.209

Gnomad OTH AF: 0.255

GnomAD2 exomes AF: 0.217 AC: 53744 AN: 248066 AF XY: 0.206

Gnomad AFR exome AF: 0.500

Gnomad AMR exome AF: 0.230

Gnomad ASJ exome AF: 0.144

Gnomad EAS exome AF: 0.238

Gnomad FIN exome AF: 0.196

Gnomad NFE exome AF: 0.210

Gnomad OTH exome AF: 0.215

GnomAD4 exome AF: 0.219 AC: 319586 AN: 1461310 Hom.: 37429 Cov.: 33 AF XY: 0.214 AC XY: 155524 AN XY: 726908

African (AFR) AF: 0.508 AC: 17019 AN: 33470

American (AMR) AF: 0.237 AC: 10606 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.145 AC: 3778 AN: 26134

East Asian (EAS) AF: 0.219 AC: 8699 AN: 39694

South Asian (SAS) AF: 0.115 AC: 9925 AN: 86246

European-Finnish (FIN) AF: 0.193 AC: 10293 AN: 53276

Middle Eastern (MID) AF: 0.199 AC: 1145 AN: 5768

European-Non Finnish (NFE) AF: 0.220 AC: 244753 AN: 1111662

Other (OTH) AF: 0.221 AC: 13368 AN: 60370

GnomAD4 genome AF: 0.284 AC: 43254 AN: 152164 Hom.: 7443 Cov.: 33 AF XY: 0.278 AC XY: 20665 AN XY: 74414

African (AFR) AF: 0.489 AC: 20297 AN: 41478

American (AMR) AF: 0.234 AC: 3576 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.146 AC: 506 AN: 3472

East Asian (EAS) AF: 0.243 AC: 1259 AN: 5180

South Asian (SAS) AF: 0.123 AC: 592 AN: 4822

European-Finnish (FIN) AF: 0.195 AC: 2063 AN: 10600

Middle Eastern (MID) AF: 0.218 AC: 64 AN: 294

European-Non Finnish (NFE) AF: 0.209 AC: 14208 AN: 67992

Other (OTH) AF: 0.259 AC: 548 AN: 2116

Alfa AF: 0.237 Hom.: 8072

Bravo AF: 0.301

Asia WGS AF: 0.210 AC: 734 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	8.5
DANN	Benign	0.66
PhyloP100		-0.049
Mutation Taster		=90/10	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: rs646558; hg19: chr11-113105907; COSMIC: COSV57517444; COSMIC: COSV57517444;