chr2-50552795-G-C

Variant names:

• chr2-50552795-G-C
• rs1553778339
• NM_001330078.2:c.1551C>G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_001330078.2(NRXN1):​c.1551C>G​(p.Ile517Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000889 in 1,461,682 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: NRXN1 NM_001330078.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.348

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 Likely_benign. Variant got -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.355645).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRXN1	NM_001330078.2	c.1551C>G	p.Ile517Met	missense_variant	Exon 9 of 23	ENST00000401669.7	NP_001317007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NRXN1	ENST00000401669.7	c.1551C>G	p.Ile517Met	missense_variant	Exon 9 of 23	5	NM_001330078.2	ENSP00000385017.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461682 Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6 AN XY: 727122

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Pitt-Hopkins-like syndrome 2 Uncertain:1

Jan 15, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with NRXN1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with methionine at codon 557 of the NRXN1 protein (p.Ile557Met). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and methionine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	0.00039	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.083	.;T;.;.;T;.;.;T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.070
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.89	D;D;D;D;D;D;D;D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.36	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	1.2	.;L;.;.;.;.;.;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.75	.;N;N;N;.;.;.;.
REVEL	Uncertain	0.36
Sift	Benign	0.15	.;T;T;T;.;.;.;.
Sift4G	Uncertain	0.058	T;T;T;T;T;T;D;D
Polyphen		0.080	.;.;B;.;.;.;.;.
Vest4		0.51
MutPred		0.75		.;Gain of disorder (P = 0.0412);.;Gain of disorder (P = 0.0412);.;.;.;.;
MVP		0.25
MPC		0.28
ClinPred		0.18	T
GERP RS		3.2
Varity_R		0.095
gMVP		0.50

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: rs1553778339; hg19: chr2-50779933;