11-113231236-G-A

Position:

• chr11-113231236-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_181351.5(NCAM1):​c.1090-409G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0069 in 1,536,138 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0052 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0071 (44 hom.)
• Consequence: NCAM1 NM_181351.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.42

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0048000515).
• BP6: Variant 11-113231236-G-A is Benign according to our data. Variant chr11-113231236-G-A is described in ClinVar as [Benign]. Clinvar id is 2642375.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 795 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NCAM1	NM_181351.5	c.1090-409G>A		intron_variant		ENST00000316851.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NCAM1	ENST00000316851.12	c.1090-409G>A		intron_variant		5	NM_181351.5	P3

Frequencies

GnomAD3 genomes AF: 0.00523 AC: 796 AN: 152196 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00138

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.0228

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00850

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00549 AC: 739 AN: 134672 Hom.: 3 AF XY: 0.00551 AC XY: 404 AN XY: 73318

Gnomad AFR exome AF: 0.00108

Gnomad AMR exome AF: 0.00306

Gnomad ASJ exome AF: 0.0189

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00156

Gnomad FIN exome AF: 0.00186

Gnomad NFE exome AF: 0.00802

Gnomad OTH exome AF: 0.00748

GnomAD4 exome AF: 0.00709 AC: 9810 AN: 1383824 Hom.: 44 Cov.: 31 AF XY: 0.00710 AC XY: 4845 AN XY: 682850

Gnomad4 AFR exome AF: 0.00111

Gnomad4 AMR exome AF: 0.00266

Gnomad4 ASJ exome AF: 0.0191

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00177

Gnomad4 FIN exome AF: 0.00224

Gnomad4 NFE exome AF: 0.00787

Gnomad4 OTH exome AF: 0.00705

GnomAD4 genome AF: 0.00522 AC: 795 AN: 152314 Hom.: 4 Cov.: 32 AF XY: 0.00447 AC XY: 333 AN XY: 74484

Gnomad4 AFR AF: 0.00137

Gnomad4 AMR AF: 0.00274

Gnomad4 ASJ AF: 0.0228

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00179

Gnomad4 NFE AF: 0.00848

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00514 Hom.: 0

Bravo AF: 0.00527

TwinsUK AF: 0.00917 AC: 34

ALSPAC AF: 0.00727 AC: 28

ExAC AF: 0.00306 AC: 76

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2022

NCAM1: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	10
DANN	Benign	0.30
DEOGEN2	Benign	0.25	T;.
FATHMM_MKL	Benign	0.078	N
LIST_S2	Benign	0.44	T;T
MetaRNN	Benign	0.0048	T;T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.30	T
Sift4G	Pathogenic	0.0	D;D
Vest4		0.22
MVP		0.73
GERP RS		2.7
gMVP		0.22

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: rs117219783; hg19: chr11-113101958;