dbSNP rs17115160: NCAM1:p.Asp260Asn (chr11-113207864-G-A) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_181351.5(NCAM1):c.778G>A(p.Asp260Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0124 in 1,611,398 control chromosomes in the GnomAD database, including 159 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/15 in silico tools predict a benign outcome for this variant. Variant has been reported in Lovd as Likely benign (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.0096 ( 6 hom., cov: 32)

Exomes 𝑓: 0.013 ( 153 hom. )

Consequence

NCAM1
NM_181351.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.72

Variant links:

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]

NCAM1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0045161247).

BP6

Variant 11-113207864-G-A is Benign according to our data. Variant chr11-113207864-G-A is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 1468 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NCAM1	NM_181351.5 link	c.778G>A	p.Asp260Asn	missense_variant	Exon 7 of 20	ENST00000316851.12	NP_851996.2	P13591-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NCAM1	ENST00000316851.12 link	c.778G>A	p.Asp260Asn	missense_variant	Exon 7 of 20	5	NM_181351.5	ENSP00000318472.8		P13591-2

Frequencies

GnomAD3 genomes

AF:

0.00965

AC:

1469

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00234

Gnomad AMI

AF:

0.0242

Gnomad AMR

AF:

0.00576

Gnomad ASJ

AF:

0.0242

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00125

Gnomad FIN

AF:

0.00848

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0157

Gnomad OTH

AF:

0.00621

GnomAD3 exomes

AF:

0.0107

AC:

2625

AN:

244738

Hom.:

AF XY:

0.0111

AC XY:

1473

AN XY:

132480

show subpopulations

Gnomad AFR exome

AF:

0.00238

Gnomad AMR exome

AF:

0.00469

Gnomad ASJ exome

AF:

0.0263

Gnomad EAS exome

AF:

0.0000563

Gnomad SAS exome

AF:

0.00220

Gnomad FIN exome

AF:

0.00956

Gnomad NFE exome

AF:

0.0165

Gnomad OTH exome

AF:

0.0102

GnomAD4 exome

AF:

0.0127

AC:

18515

AN:

1459126

Hom.:

153

Cov.:

AF XY:

0.0129

AC XY:

9358

AN XY:

725440

show subpopulations

Gnomad4 AFR exome

AF:

0.00221

Gnomad4 AMR exome

AF:

0.00495

Gnomad4 ASJ exome

AF:

0.0263

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00220

Gnomad4 FIN exome

AF:

0.00890

Gnomad4 NFE exome

AF:

0.0145

Gnomad4 OTH exome

AF:

0.0112

GnomAD4 genome

AF:

0.00964

AC:

1468

AN:

152272

Hom.:

Cov.:

AF XY:

0.00870

AC XY:

648

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.00233

Gnomad4 AMR

AF:

0.00575

Gnomad4 ASJ

AF:

0.0242

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00125

Gnomad4 FIN

AF:

0.00848

Gnomad4 NFE

AF:

0.0157

Gnomad4 OTH

AF:

0.00615

Alfa

AF:

0.0151

Hom.:

Bravo

AF:

0.00920

TwinsUK

AF:

0.0105

AC:

ALSPAC

AF:

0.0148

AC:

ESP6500AA

AF:

0.00125

AC:

ESP6500EA

AF:

0.0139

AC:

116

ExAC

AF:

0.0113

AC:

1368

Asia WGS

AF:

0.00231

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Benign

0.20

DEOGEN2

Benign

0.22

.;T;T;T;.;.;.;T;.;.;.

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.25

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.87

D;D;D;D;D;D;D;D;D;D;D

MetaRNN

Benign

0.0045

T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

PrimateAI

Benign

0.30

REVEL

Benign

0.051

Sift4G

Benign

0.97

T;T;T;T;T;T;T;T;T;T;T

Polyphen

0.11, 0.21, 0.26, 0.32

.;.;.;.;.;.;.;B;B;B;B

Vest4

0.079

ClinPred

0.0051

GERP RS

4.7

Varity_R

0.19

gMVP

0.79

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over