rs201336161

Positions:

chr2-50091446-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS1

The NM_001330078.2(NRXN1):c.3595G>A(p.Ala1199Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000141 in 1,614,048 control chromosomes in the GnomAD database, including 1 homozygotes. 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00014 ( 1 hom. )

Consequence

NRXN1
NM_001330078.2 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 2.33

Variant links:

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]

NRXN1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009151369).

BP6

Variant 2-50091446-C-T is Benign according to our data. Variant chr2-50091446-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 206263.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000131 (20/152258) while in subpopulation EAS AF= 0.00367 (19/5172). AF 95% confidence interval is 0.00241. There are 0 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NRXN1	NM_001330078.2 linkuse as main transcript	c.3595G>A	p.Ala1199Thr	missense_variant	19/23	ENST00000401669.7	NP_001317007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NRXN1	ENST00000401669.7 linkuse as main transcript	c.3595G>A	p.Ala1199Thr	missense_variant	19/23	5	NM_001330078.2	ENSP00000385017	A1

Frequencies

GnomAD3 genomes

AF:

0.000131

AC:

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00367

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000402

AC:

101

AN:

251428

Hom.:

AF XY:

0.000405

AC XY:

AN XY:

135880

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00538

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000142

AC:

208

AN:

1461790

Hom.:

Cov.:

AF XY:

0.000133

AC XY:

AN XY:

727200

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00479

Gnomad4 SAS exome

AF:

0.0000927

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.000131

AC:

AN:

152258

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00367

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000509

Hom.:

Bravo

AF:

0.000272

ExAC

AF:

0.000338

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 13, 2019

This variant is associated with the following publications: (PMID: 24832020, 33343614) -

Pitt-Hopkins-like syndrome 2

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 08, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

DANN

Benign

0.33

DEOGEN2

Benign

0.15

.;T;.;.;T;.;.;T;.

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.20

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.88

D;D;D;D;D;D;D;D;D

M_CAP

Benign

0.011

MetaRNN

Benign

0.0092

T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.3

.;.;.;N;N;.;.;.;.

MutationTaster

Benign

0.93

N;N;N;N;N;N;N;N

PrimateAI

Uncertain

0.64

PROVEAN

Benign

1.6

.;N;N;N;.;N;.;.;.

REVEL

Benign

0.23

Sift

Benign

0.76

.;T;T;T;.;T;.;.;.

Sift4G

Benign

0.59

T;T;T;T;T;T;T;T;T

Polyphen

0.015, 0.019

.;.;B;.;B;.;.;.;.

Vest4

0.32

MVP

0.13

MPC

0.73

ClinPred

0.036

GERP RS

5.5

Varity_R

0.097

gMVP

0.43

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over