rs6958498

Variant names:

• chr7-108194169-G-C
• rs6958498
• NM_001037132.4:c.1633C>G

Your query was ambiguous. Multiple possible variants found:

• chr7-108194169-G-C
• chr7-108194169-G-A
• chr7-108194169-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001037132.4(NRCAM):​c.1633C>G​(p.Pro545Ala) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.766 in 1,612,338 control chromosomes in the GnomAD database, including 477,553 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.71 (39332 hom., cov: 33)
  • Exomes 𝑓: 0.77 (438221 hom.)
• Consequence: NRCAM NM_001037132.4 missense, splice_region
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 7.70
• Publications: 39 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.1271684E-6).
• BP6: Variant 7-108194169-G-C is Benign according to our data. Variant chr7-108194169-G-C is described in ClinVar as Benign. ClinVar VariationId is 1250798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.858 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001037132.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRCAM	NM_001037132.4	MANE Select	c.1633C>G	p.Pro545Ala	missense splice_region	Exon 17 of 33	NP_001032209.1	Q92823-1
	NRCAM	NM_001371156.1		c.1633C>G	p.Pro545Ala	missense splice_region	Exon 17 of 33	NP_001358085.1
	NRCAM	NM_001371131.1		c.1633C>G	p.Pro545Ala	missense splice_region	Exon 18 of 34	NP_001358060.1	Q92823-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRCAM	ENST00000379028.8	TSL:5 MANE Select	c.1633C>G	p.Pro545Ala	missense splice_region	Exon 17 of 33	ENSP00000368314.3	Q92823-1
	NRCAM	ENST00000379024.8	TSL:1	c.1576C>G	p.Pro526Ala	missense splice_region	Exon 16 of 30	ENSP00000368310.4	Q92823-6
	NRCAM	ENST00000351718.8	TSL:1	c.1615C>G	p.Pro539Ala	missense splice_region	Exon 16 of 28	ENSP00000325269.6	Q92823-4

Frequencies

GnomAD3 genomes AF: 0.707 AC: 107532 AN: 151996 Hom.: 39325 Cov.: 33

Gnomad AFR AF: 0.500

Gnomad AMI AF: 0.853

Gnomad AMR AF: 0.807

Gnomad ASJ AF: 0.760

Gnomad EAS AF: 0.879

Gnomad SAS AF: 0.698

Gnomad FIN AF: 0.785

Gnomad MID AF: 0.693

Gnomad NFE AF: 0.782

Gnomad OTH AF: 0.727

GnomAD2 exomes AF: 0.768 AC: 192941 AN: 251268 AF XY: 0.766

Gnomad AFR exome AF: 0.493

Gnomad AMR exome AF: 0.856

Gnomad ASJ exome AF: 0.750

Gnomad EAS exome AF: 0.882

Gnomad FIN exome AF: 0.785

Gnomad NFE exome AF: 0.778

Gnomad OTH exome AF: 0.779

GnomAD4 exome AF: 0.772 AC: 1127959 AN: 1460224 Hom.: 438221 Cov.: 48 AF XY: 0.770 AC XY: 559601 AN XY: 726482

African (AFR) AF: 0.486 AC: 16263 AN: 33436

American (AMR) AF: 0.849 AC: 37946 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.757 AC: 19768 AN: 26118

East Asian (EAS) AF: 0.872 AC: 34624 AN: 39688

South Asian (SAS) AF: 0.704 AC: 60711 AN: 86198

European-Finnish (FIN) AF: 0.784 AC: 41856 AN: 53418

Middle Eastern (MID) AF: 0.683 AC: 3935 AN: 5764

European-Non Finnish (NFE) AF: 0.781 AC: 866881 AN: 1110544

Other (OTH) AF: 0.762 AC: 45975 AN: 60344

GnomAD4 genome AF: 0.707 AC: 107579 AN: 152114 Hom.: 39332 Cov.: 33 AF XY: 0.712 AC XY: 52963 AN XY: 74358

African (AFR) AF: 0.500 AC: 20731 AN: 41466

American (AMR) AF: 0.807 AC: 12340 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.760 AC: 2637 AN: 3472

East Asian (EAS) AF: 0.879 AC: 4544 AN: 5170

South Asian (SAS) AF: 0.698 AC: 3365 AN: 4824

European-Finnish (FIN) AF: 0.785 AC: 8307 AN: 10588

Middle Eastern (MID) AF: 0.690 AC: 203 AN: 294

European-Non Finnish (NFE) AF: 0.782 AC: 53146 AN: 67986

Other (OTH) AF: 0.726 AC: 1528 AN: 2106

Alfa AF: 0.769 Hom.: 31079

Bravo AF: 0.703

TwinsUK AF: 0.785 AC: 2910

ALSPAC AF: 0.781 AC: 3011

ESP6500AA AF: 0.507 AC: 2232

ESP6500EA AF: 0.780 AC: 6706

ExAC AF: 0.756 AC: 91797

Asia WGS AF: 0.747 AC: 2596 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.44
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Uncertain	0.77	D
Eigen	Benign	0.026
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0000031	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		7.7
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Benign	0.17
Sift	Benign	0.24	T
Sift4G	Benign	0.48	T
Polyphen		0.0030	B
Vest4		0.064
MPC		0.23
ClinPred		0.11	T
GERP RS		4.8
Varity_R		0.25
gMVP		0.65
Mutation Taster		=94/6	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs6958498; hg19: chr7-107834613; COSMIC: COSV61033740; COSMIC: COSV61033740;