11-64651496-T-G

Variant names:

• chr11-64651496-T-G
• rs765465352
• NM_015080.4:c.2677A>C

Variant summary

Our verdict is Likely benign. The variant received -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. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M893V) has been classified as Uncertain significance.

• 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
• Publications: 2 publications found

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-AS1 (HGNC:40416): (NRXN2 antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -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 rank	MANE	Protein	UniProt
NRXN2	NM_015080.4	c.2677A>C	p.Met893Leu	missense_variant	Exon 14 of 23	ENST00000265459.11	NP_055895.1

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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;.
PhyloP100		2.0
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
Mutation Taster		=95/5	polymorphism

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: rs765465352; hg19: chr11-64418968;