11-64651496-T-G

Position:

• chr11-64651496-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_015080.4(NRXN2):​c.2677A>C​(p.Met893Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. 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: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.00

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]

NRXN2 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06611875).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NRXN2	NM_015080.4	c.2677A>C	p.Met893Leu	missense_variant	14/23	ENST00000265459.11	NP_055895.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NRXN2	ENST00000265459.11	c.2677A>C	p.Met893Leu	missense_variant	14/23	5	NM_015080.4	ENSP00000265459.5
NRXN2	ENST00000704782.1	c.2686A>C	p.Met896Leu	missense_variant	13/22			ENSP00000516031.1
NRXN2	ENST00000704781.1	c.2686A>C	p.Met896Leu	missense_variant	13/22			ENSP00000516029.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 20, 2024

The c.2677A>C (p.M893L) alteration is located in exon 14 (coding exon 13) of the NRXN2 gene. This alteration results from a A to C substitution at nucleotide position 2677, causing the methionine (M) at amino acid position 893 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	21
DANN	Benign	0.91
DEOGEN2	Benign	0.0033	T;.;T;.
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.76	D
LIST_S2	Uncertain	0.91	.;D;D;D
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.066	T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-0.81	N;.;N;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.050	N;N;N;N
REVEL	Benign	0.18
Sift	Benign	0.41	T;T;T;T
Sift4G	Benign	0.32	T;T;T;T
Polyphen		0.0	B;B;B;.
Vest4		0.13
MutPred		0.52		Loss of methylation at K897 (P = 0.0764);.;Loss of methylation at K897 (P = 0.0764);.;
MVP		0.11
MPC		0.85
ClinPred		0.40	T
GERP RS		4.4
Varity_R		0.11
gMVP		0.35

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

Publications

LitVar

Other links and lift over

dbSNP: rs765465352; hg19: chr11-64418968;