11-113246105-C-A

Variant names:

• chr11-113246105-C-A
• rs12222469
• NM_181351.5:c.1826-263C>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_181351.5(NCAM1):​c.1826-263C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0913 in 517,088 control chromosomes in the GnomAD database, including 4,553 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 0.079 (1006 hom., cov: 33)
  • Exomes 𝑓: 0.096 (3547 hom.)
• Consequence: NCAM1 NM_181351.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.58
• Publications: 1 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.386 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181351.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCAM1	NM_181351.5	MANE Select	c.1826-263C>A		intron	N/A	NP_851996.2
	NCAM1	NM_001400624.1		c.1826-9772C>A		intron	N/A	NP_001387553.1
	NCAM1	NM_001400620.1		c.1811-9772C>A		intron	N/A	NP_001387549.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCAM1	ENST00000316851.12	TSL:5 MANE Select	c.1826-263C>A		intron	N/A	ENSP00000318472.8
	NCAM1	ENST00000533073.5	TSL:1	c.323-9772C>A		intron	N/A	ENSP00000486406.1
	NCAM1	ENST00000619839.4	TSL:5	c.1904-263C>A		intron	N/A	ENSP00000480132.1

Frequencies

GnomAD3 genomes AF: 0.0796 AC: 12103 AN: 152120 Hom.: 1009 Cov.: 33

Gnomad AFR AF: 0.0385

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.182

Gnomad ASJ AF: 0.0533

Gnomad EAS AF: 0.401

Gnomad SAS AF: 0.166

Gnomad FIN AF: 0.0571

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0566

Gnomad OTH AF: 0.0840

GnomAD4 exome AF: 0.0962 AC: 35094 AN: 364850 Hom.: 3547 Cov.: 0 AF XY: 0.0977 AC XY: 18500 AN XY: 189374

African (AFR) AF: 0.0345 AC: 384 AN: 11132

American (AMR) AF: 0.192 AC: 2518 AN: 13146

Ashkenazi Jewish (ASJ) AF: 0.0483 AC: 576 AN: 11918

East Asian (EAS) AF: 0.406 AC: 11434 AN: 28188

South Asian (SAS) AF: 0.147 AC: 3621 AN: 24626

European-Finnish (FIN) AF: 0.0573 AC: 1474 AN: 25726

Middle Eastern (MID) AF: 0.0644 AC: 108 AN: 1676

European-Non Finnish (NFE) AF: 0.0581 AC: 13145 AN: 226320

Other (OTH) AF: 0.0829 AC: 1834 AN: 22118

GnomAD4 genome AF: 0.0794 AC: 12094 AN: 152238 Hom.: 1006 Cov.: 33 AF XY: 0.0859 AC XY: 6390 AN XY: 74414

African (AFR) AF: 0.0383 AC: 1593 AN: 41550

American (AMR) AF: 0.182 AC: 2778 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0533 AC: 185 AN: 3470

East Asian (EAS) AF: 0.400 AC: 2068 AN: 5170

South Asian (SAS) AF: 0.166 AC: 800 AN: 4820

European-Finnish (FIN) AF: 0.0571 AC: 605 AN: 10604

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0565 AC: 3846 AN: 68014

Other (OTH) AF: 0.0841 AC: 178 AN: 2116

Alfa AF: 0.0219 Hom.: 13

Bravo AF: 0.0869

Asia WGS AF: 0.256 AC: 889 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	18
DANN	Benign	0.75
PhyloP100		2.6
Mutation Taster		=99/1	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: rs12222469; hg19: chr11-113116827;