rs762326241

chr2-50538388-G-Achr2-50538388-G-Cchr2-50538388-G-T

Variant summary

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

The NM_001330078.2(NRXN1):c.2008C>T(p.Pro670Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000103 in 1,461,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. P670A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: NRXN1 NM_001330078.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.85

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=0.38269567).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NRXN1	NM_001330078.2	c.2008C>T	p.Pro670Ser	missense_variant	10/23	ENST00000401669.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NRXN1	ENST00000401669.7	c.2008C>T	p.Pro670Ser	missense_variant	10/23	5	NM_001330078.2	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000802 AC: 2 AN: 249346 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135260

Gnomad AFR exome AF: 0.0000645

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000555

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461694 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727126

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000282 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 21, 2021

The c.2128C>T (p.P710S) alteration is located in exon 11 (coding exon 10) of the NRXN1 gene. This alteration results from a C to T substitution at nucleotide position 2128, causing the proline (P) at amino acid position 710 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Pitt-Hopkins-like syndrome 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 15, 2023

This variant has not been reported in the literature in individuals affected with NRXN1-related conditions. 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant  is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 2233747). This variant is present in population databases (rs762326241, gnomAD 0.007%). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 710 of the NRXN1 protein (p.Pro710Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.043	T
BayesDel_noAF	Uncertain	0.010
Cadd	Uncertain	24
Dann	Uncertain	0.99
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;D;D;D;D;D;D;D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.38	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.71	T
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.76	T
Sift4G	Benign	0.95	T;T;T;T;T;T;T;T
Polyphen		0.42	.;.;B;.;.;.;.;.
Vest4		0.42
MutPred		0.46		.;Loss of methylation at K669 (P = 0.0692);.;Loss of methylation at K669 (P = 0.0692);.;.;.;.;
MVP		0.33
MPC		0.42
ClinPred		0.61	D
GERP RS		5.2
Varity_R		0.16
gMVP		0.65

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: rs762326241; hg19: chr2-50765526;