11-64607521-C-T

Variant names:

• chr11-64607521-C-T
• rs748840734
• NM_015080.4:c.4814G>A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_015080.4(NRXN2):​c.4814G>A​(p.Gly1605Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000488 in 1,433,634 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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. G1605R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000049 (0 hom.)
• Consequence: NRXN2 NM_015080.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.477

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.047447383).
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRXN2	NM_015080.4	c.4814G>A	p.Gly1605Asp	missense_variant	Exon 23 of 23	ENST00000265459.11	NP_055895.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NRXN2	ENST00000265459.11	c.4814G>A	p.Gly1605Asp	missense_variant	Exon 23 of 23	5	NM_015080.4	ENSP00000265459.5
NRXN2	ENST00000704782.1	c.4823G>A	p.Gly1608Asp	missense_variant	Exon 22 of 22			ENSP00000516031.1
NRXN2	ENST00000704781.1	c.4262-21G>A		intron_variant	Intron 21 of 21			ENSP00000516029.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.0000344 AC: 7 AN: 203304 Hom.: 0 AF XY: 0.0000355 AC XY: 4 AN XY: 112804

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000127

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000832

Gnomad NFE exome AF: 0.0000225

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000488 AC: 7 AN: 1433634 Hom.: 0 Cov.: 33 AF XY: 0.00000563 AC XY: 4 AN XY: 711044

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000701

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000239

Gnomad4 NFE exome AF: 9.08e-7

Gnomad4 OTH exome AF: 0.0000337

GnomAD4 genome Cov.: 30

Alfa AF: 0.0000509 Hom.: 0

ExAC AF: 0.0000170 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 14, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4814G>A (p.G1605D) alteration is located in exon 23 (coding exon 22) of the NRXN2 gene. This alteration results from a G to A substitution at nucleotide position 4814, causing the glycine (G) at amino acid position 1605 to be replaced by an aspartic acid (D). 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	-0.30	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.096	T;T;.;T;.
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.58	D
LIST_S2	Uncertain	0.90	D;.;D;D;D
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.047	T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.55	.;N;.;N;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-1.2	N;N;N;N;N
REVEL	Benign	0.10
Sift	Benign	0.85	T;T;T;T;T
Sift4G	Benign	0.64	T;T;T;T;T
Polyphen		0.012	B;P;B;P;.
Vest4		0.10
MutPred		0.10		.;Gain of solvent accessibility (P = 0.1014);.;Gain of solvent accessibility (P = 0.1014);.;
MVP		0.28
MPC		1.3
ClinPred		0.041	T
GERP RS		3.8
Varity_R		0.10
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs748840734; hg19: chr11-64374993;