rs2072546

Variant names:

• chr7-108232372-G-A
• rs2072546
• NM_001037132.4:c.381C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_001037132.4(NRCAM):​c.381C>T​(p.Asn127Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.152 in 1,609,834 control chromosomes in the GnomAD database, including 25,042 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 0.14 (2362 hom., cov: 32)
  • Exomes 𝑓: 0.15 (22680 hom.)
• Consequence: NRCAM NM_001037132.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.651
• Publications: 20 publications found

Genes affected

NRCAM (HGNC:7994): (neuronal cell adhesion molecule) Cell adhesion molecules (CAMs) are members of the immunoglobulin superfamily. This gene encodes a neuronal cell adhesion molecule with multiple immunoglobulin-like C2-type domains and fibronectin type-III domains. This ankyrin-binding protein is involved in neuron-neuron adhesion and promotes directional signaling during axonal cone growth. This gene is also expressed in non-neural tissues and may play a general role in cell-cell communication via signaling from its intracellular domain to the actin cytoskeleton during directional cell migration. Allelic variants of this gene have been associated with autism and addiction vulnerability. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

NRCAM Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with neuromuscular and skeletal abnormalities

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP7: Synonymous conserved (PhyloP=-0.651 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.544 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRCAM	NM_001037132.4	c.381C>T	p.Asn127Asn	synonymous_variant	Exon 7 of 33	ENST00000379028.8	NP_001032209.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NRCAM	ENST00000379028.8	c.381C>T	p.Asn127Asn	synonymous_variant	Exon 7 of 33	5	NM_001037132.4	ENSP00000368314.3

Frequencies

GnomAD3 genomes AF: 0.136 AC: 20714 AN: 151990 Hom.: 2361 Cov.: 32

Gnomad AFR AF: 0.0286

Gnomad AMI AF: 0.270

Gnomad AMR AF: 0.245

Gnomad ASJ AF: 0.112

Gnomad EAS AF: 0.560

Gnomad SAS AF: 0.220

Gnomad FIN AF: 0.153

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.136

Gnomad OTH AF: 0.137

GnomAD2 exomes AF: 0.205 AC: 50713 AN: 246956 AF XY: 0.202

Gnomad AFR exome AF: 0.0259

Gnomad AMR exome AF: 0.364

Gnomad ASJ exome AF: 0.110

Gnomad EAS exome AF: 0.578

Gnomad FIN exome AF: 0.155

Gnomad NFE exome AF: 0.138

Gnomad OTH exome AF: 0.173

GnomAD4 exome AF: 0.154 AC: 224038 AN: 1457726 Hom.: 22680 Cov.: 32 AF XY: 0.156 AC XY: 113080 AN XY: 725132

African (AFR) AF: 0.0208 AC: 692 AN: 33224

American (AMR) AF: 0.347 AC: 15253 AN: 43928

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 2914 AN: 26006

East Asian (EAS) AF: 0.545 AC: 21517 AN: 39516

South Asian (SAS) AF: 0.231 AC: 19690 AN: 85396

European-Finnish (FIN) AF: 0.157 AC: 8402 AN: 53370

Middle Eastern (MID) AF: 0.161 AC: 910 AN: 5638

European-Non Finnish (NFE) AF: 0.131 AC: 145430 AN: 1110434

Other (OTH) AF: 0.153 AC: 9230 AN: 60214

GnomAD4 genome AF: 0.136 AC: 20716 AN: 152108 Hom.: 2362 Cov.: 32 AF XY: 0.143 AC XY: 10622 AN XY: 74330

African (AFR) AF: 0.0286 AC: 1186 AN: 41540

American (AMR) AF: 0.245 AC: 3746 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 388 AN: 3472

East Asian (EAS) AF: 0.561 AC: 2893 AN: 5154

South Asian (SAS) AF: 0.219 AC: 1054 AN: 4812

European-Finnish (FIN) AF: 0.153 AC: 1616 AN: 10580

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.136 AC: 9251 AN: 67976

Other (OTH) AF: 0.134 AC: 283 AN: 2106

Alfa AF: 0.139 Hom.: 4772

Bravo AF: 0.141

Asia WGS AF: 0.295 AC: 1024 AN: 3478

EpiCase AF: 0.141

EpiControl AF: 0.139

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	0.15
DANN	Benign	0.73
PhyloP100		-0.65
Mutation Taster		=100/0	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: rs2072546; hg19: chr7-107872816; COSMIC: COSV61037084; COSMIC: COSV61037084;