11-113260194-C-T

Position:

• chr11-113260194-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_181351.5(NCAM1):​c.2002C>T​(p.His668Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NCAM1 NM_181351.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.83

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29102433).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NCAM1	NM_181351.5	c.2002C>T	p.His668Tyr	missense_variant	17/20	ENST00000316851.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NCAM1	ENST00000316851.12	c.2002C>T	p.His668Tyr	missense_variant	17/20	5	NM_181351.5	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 05, 2023

The c.2080C>T (p.H694Y) alteration is located in exon 18 (coding exon 18) of the NCAM1 gene. This alteration results from a C to T substitution at nucleotide position 2080, causing the histidine (H) at amino acid position 694 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.083	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.25	.;T;T;T;.;.;.;T;T;.;.;.;.
Eigen	Benign	0.019
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.27	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.70	T
REVEL	Benign	0.062
Sift4G	Benign	0.52	T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0020, 0.0060, 0.015	.;.;.;.;.;.;.;B;.;B;B;.;.
Vest4		0.21
MutPred		0.54		.;.;Gain of phosphorylation at H668 (P = 0.0207);.;.;.;.;Gain of phosphorylation at H668 (P = 0.0207);.;.;.;.;.;
MVP		0.17
ClinPred		0.95	D
GERP RS		5.5
Varity_R		0.42
gMVP		0.54

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-113130916;