11-64660440-T-C

Variant names:

• chr11-64660440-T-C
• rs138291758
• NM_015080.4:c.2281A>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_015080.4(NRXN2):​c.2281A>G​(p.Met761Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NRXN2 NM_015080.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.14

Genes affected

NRXN2 (HGNC:8009): (neurexin 2) This gene encodes a member of the neurexin gene family. The products of these genes function as cell adhesion molecules and receptors in the vertebrate nervous system. These genes utilize two promoters. The majority of transcripts are produced from the upstream promoter and encode alpha-neurexin isoforms while a smaller number of transcripts are produced from the downstream promoter and encode beta-neuresin isoforms. The alpha-neurexins contain epidermal growth factor-like (EGF-like) sequences and laminin G domains, and have been shown to interact with neurexophilins. The beta-neurexins lack EGF-like sequences and contain fewer laminin G domains than alpha-neurexins. Alternative splicing and the use of alternative promoters may generate thousands of transcript variants (PMID: 12036300, PMID: 11944992).[provided by RefSeq, Jun 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRXN2	NM_015080.4	c.2281A>G	p.Met761Val	missense_variant	Exon 11 of 23	ENST00000265459.11	NP_055895.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NRXN2	ENST00000265459.11	c.2281A>G	p.Met761Val	missense_variant	Exon 11 of 23	5	NM_015080.4	ENSP00000265459.5
NRXN2	ENST00000704782.1	c.2281A>G	p.Met761Val	missense_variant	Exon 10 of 22			ENSP00000516031.1
NRXN2	ENST00000704781.1	c.2281A>G	p.Met761Val	missense_variant	Exon 10 of 22			ENSP00000516029.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T;.;T;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.86	.;D;D;D
M_CAP	Benign	0.042	D
MetaRNN	Uncertain	0.46	T;T;T;T
MetaSVM	Uncertain	0.21	D
MutationAssessor	Benign	1.7	L;.;L;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.9	D;D;D;D
REVEL	Pathogenic	0.68
Sift	Benign	0.061	T;T;T;T
Sift4G	Uncertain	0.042	D;D;D;D
Polyphen		0.97	D;P;D;.
Vest4		0.42
MutPred		0.67		Loss of disorder (P = 0.0707);.;Loss of disorder (P = 0.0707);.;
MVP		0.55
MPC		0.64
ClinPred		0.93	D
GERP RS		4.6
Varity_R		0.24
gMVP		0.66

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: rs138291758; hg19: chr11-64427912;