rs1011679353

Positions:

• chr2-51027602-C-A
• chr2-51027602-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001330078.2(NRXN1):​c.672G>T​(p.Glu224Asp) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: NRXN1 NM_001330078.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.143

Genes affected

NRXN1 (HGNC:8008): (neurexin 1) This gene encodes a single-pass type I membrane protein that belongs to the neurexin family. Neurexins are cell-surface receptors that bind neuroligins to form Ca(2+)-dependent neurexin/neuroligin complexes at synapses in the central nervous system. This complex is required for efficient neurotransmission and is involved in the formation of synaptic contacts. Three members of this gene family have been studied in detail and are estimated to generate over 3,000 variants through the use of two alternative promoters (alpha and beta) and extensive alternative splicing in each family member. Recently, a third promoter (gamma) was identified for this gene in the 3' region. Mutations in this gene are associated with Pitt-Hopkins-like syndrome-2 and may contribute to susceptibility to schizophrenia. [provided by RefSeq, Aug 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.092844635).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NRXN1	NM_001330078.2	c.672G>T	p.Glu224Asp	missense_variant	2/23	ENST00000401669.7	NP_001317007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NRXN1	ENST00000401669.7	c.672G>T	p.Glu224Asp	missense_variant	2/23	5	NM_001330078.2	ENSP00000385017.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Pitt-Hopkins-like syndrome 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 02, 2023

ClinVar contains an entry for this variant (Variation ID: 581102). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The aspartic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant has not been reported in the literature in individuals affected with NRXN1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 224 of the NRXN1 protein (p.Glu224Asp). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	15
DANN	Benign	0.93
DEOGEN2	Benign	0.0038	.;T;.;.;T;.;T;.;T;T;.
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.82	T;T;T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.093	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.055	N;N;N;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.13	.;N;N;N;N;.;.;.;N;.;.
REVEL	Benign	0.032
Sift	Benign	0.65	.;T;T;T;T;.;.;.;T;.;.
Sift4G	Benign	0.65	T;T;T;T;T;T;T;T;T;.;T
Polyphen		0.022, 0.0	.;B;B;.;.;.;.;.;.;.;.
Vest4		0.20
MutPred		0.33		Loss of solvent accessibility (P = 0.3473);Loss of solvent accessibility (P = 0.3473);Loss of solvent accessibility (P = 0.3473);Loss of solvent accessibility (P = 0.3473);Loss of solvent accessibility (P = 0.3473);Loss of solvent accessibility (P = 0.3473);Loss of solvent accessibility (P = 0.3473);.;Loss of solvent accessibility (P = 0.3473);Loss of solvent accessibility (P = 0.3473);Loss of solvent accessibility (P = 0.3473);
MVP		0.30
MPC		0.54
ClinPred		0.062	T
GERP RS		2.6
Varity_R		0.077
gMVP		0.42

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: rs1011679353; hg19: chr2-51254740; COSMIC: COSV101278339; COSMIC: COSV101278339;