21-21284309-T-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_004540.5(NCAM2):c.246T>C(p.Asn82=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00209 in 1,612,448 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (6 hom.)
• Consequence: NCAM2 NM_004540.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.62

Genes affected

NCAM2 (HGNC:7657): (neural cell adhesion molecule 2) The protein encoded by this gene belongs to the immunoglobulin superfamily. It is a type I membrane protein and may function in selective fasciculation and zone-to-zone projection of the primary olfactory axons. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 21-21284309-T-C is Benign according to our data. Variant chr21-21284309-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 3042988.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-1.62 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NCAM2	NM_004540.5	c.246T>C	p.Asn82=	synonymous_variant	3/18	ENST00000400546.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NCAM2	ENST00000400546.6	c.246T>C	p.Asn82=	synonymous_variant	3/18	1	NM_004540.5	P1
NCAM2	ENST00000284894.8	c.192T>C	p.Asn64=	synonymous_variant	2/17	5
NCAM2	ENST00000486367.1	n.261T>C		non_coding_transcript_exon_variant	3/5	3

Frequencies

GnomAD3 genomes AF: 0.00175 AC: 265 AN: 151820 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000658

Gnomad ASJ AF: 0.000866

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00435

Gnomad FIN AF: 0.00283

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00274

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00203 AC: 506 AN: 249086 Hom.: 1 AF XY: 0.00229 AC XY: 310 AN XY: 135146

Gnomad AFR exome AF: 0.000388

Gnomad AMR exome AF: 0.000377

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.000112

Gnomad SAS exome AF: 0.00357

Gnomad FIN exome AF: 0.00283

Gnomad NFE exome AF: 0.00258

Gnomad OTH exome AF: 0.00165

GnomAD4 exome AF: 0.00213 AC: 3109 AN: 1460510 Hom.: 6 Cov.: 31 AF XY: 0.00226 AC XY: 1640 AN XY: 726604

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000403

Gnomad4 ASJ exome AF: 0.00115

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00387

Gnomad4 FIN exome AF: 0.00300

Gnomad4 NFE exome AF: 0.00215

Gnomad4 OTH exome AF: 0.00239

GnomAD4 genome AF: 0.00174 AC: 265 AN: 151938 Hom.: 0 Cov.: 32 AF XY: 0.00210 AC XY: 156 AN XY: 74250

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.000657

Gnomad4 ASJ AF: 0.000866

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00435

Gnomad4 FIN AF: 0.00283

Gnomad4 NFE AF: 0.00274

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00232 Hom.: 3

Bravo AF: 0.00115

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00240

EpiControl AF: 0.00154

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

NCAM2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 28, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	0.13
Dann	Benign	0.56

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: rs182642680; hg19: chr21-22656629; COSMIC: COSV53087717;