rs35576001

chr11-113206082-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PP2 BP4_Strong BS1 BS2

The NM_181351.5(NCAM1):c.530G>A(p.Arg177Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00146 in 1,613,844 control chromosomes in the GnomAD database, including 25 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 0.0072 (14 hom., cov: 32)
  • Exomes 𝑓: 0.00086 (11 hom.)
• Consequence: NCAM1 NM_181351.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.96

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

Verdict is Benign. Variant got -11 ACMG points.

• PP2: Missense variant where missense usually causes diseases, NCAM1
• BP4: Computational evidence support a benign effect (MetaRNN=0.0080245435).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00722 (1098/152170) while in subpopulation AFR AF= 0.0249 (1035/41528). AF 95% confidence interval is 0.0237. There are 14 homozygotes in gnomad4. There are 524 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1097 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NCAM1	NM_181351.5	c.530G>A	p.Arg177Gln	missense_variant	5/20	ENST00000316851.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NCAM1	ENST00000316851.12	c.530G>A	p.Arg177Gln	missense_variant	5/20	5	NM_181351.5	P3

Frequencies

GnomAD3 genomes AF: 0.00721 AC: 1097 AN: 152052 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.0249

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00624

GnomAD3 exomes AF: 0.00199 AC: 497 AN: 249272 Hom.: 6 AF XY: 0.00163 AC XY: 221 AN XY: 135238

Gnomad AFR exome AF: 0.0260

Gnomad AMR exome AF: 0.00165

Gnomad ASJ exome AF: 0.000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.0000973

Gnomad OTH exome AF: 0.00182

GnomAD4 exome AF: 0.000859 AC: 1255 AN: 1461674 Hom.: 11 Cov.: 31 AF XY: 0.000800 AC XY: 582 AN XY: 727118

Gnomad4 AFR exome AF: 0.0265

Gnomad4 AMR exome AF: 0.00206

Gnomad4 ASJ exome AF: 0.00111

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000103

Gnomad4 OTH exome AF: 0.00182

GnomAD4 genome AF: 0.00722 AC: 1098 AN: 152170 Hom.: 14 Cov.: 32 AF XY: 0.00704 AC XY: 524 AN XY: 74390

Gnomad4 AFR AF: 0.0249

Gnomad4 AMR AF: 0.00229

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00618

Alfa AF: 0.00382 Hom.: 2

Bravo AF: 0.00820

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0269 AC: 107

ESP6500EA AF: 0.000601 AC: 5

ExAC AF: 0.00245 AC: 296

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.28
Cadd	Pathogenic	26
Dann	Pathogenic	1.0
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D
MetaRNN	Benign	0.0080	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.71	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.62	T
Sift4G	Benign	0.12	T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.78, 0.99, 0.98	.;.;.;.;.;.;.;P;D;D;D
Vest4		0.23
MVP		0.41
ClinPred		0.029	T
GERP RS		4.8
Varity_R		0.44
gMVP		0.80

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

Other links and lift over

dbSNP: rs35576001; hg19: chr11-113076804; COSMIC: COSV57512231; COSMIC: COSV57512231;