rs200935246

Variant names:

• chr2-50053388-C-A
• rs200935246
• NM_001330078.2:c.4011G>T

Your query was ambiguous. Multiple possible variants found:

• chr2-50053388-C-A
• chr2-50053388-C-G
• chr2-50053388-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_001330078.2(NRXN1):​c.4011G>T​(p.Glu1337Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,702 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: NRXN1 NM_001330078.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.81
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• chromosome 2p16.3 deletion syndrome

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Pitt-Hopkins-like syndrome 2

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• autism

  Inheritance: AD Classification: MODERATE Submitted by: G2P
• schizophrenia

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13474858).
• BP6: Variant 2-50053388-C-A is Benign according to our data. Variant chr2-50053388-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3682385.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRXN1	NM_001330078.2	c.4011G>T	p.Glu1337Asp	missense_variant	Exon 21 of 23	ENST00000401669.7	NP_001317007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NRXN1	ENST00000401669.7	c.4011G>T	p.Glu1337Asp	missense_variant	Exon 21 of 23	5	NM_001330078.2	ENSP00000385017.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251158 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461702 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727150

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111908

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Pitt-Hopkins-like syndrome 2 Benign:1

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.019	.;T;.;.;.;.;.;.;T;.
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.011
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.13	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	-0.20	.;.;.;N;.;.;.;.;.;.
PhyloP100		2.8
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.95	.;N;N;N;.;.;N;.;.;.
REVEL	Benign	0.12
Sift	Benign	0.27	.;T;T;T;.;.;T;.;.;.
Sift4G	Benign	0.53	T;T;T;T;T;T;T;T;T;T
Polyphen		0.0060	.;.;B;.;.;.;.;.;.;.
Vest4		0.26
MutPred		0.20		.;Loss of catalytic residue at E1307 (P = 0.1072);.;.;.;.;.;.;.;.;
MVP		0.34
MPC		0.69
ClinPred		0.47	T
GERP RS		4.8
Varity_R		0.14
gMVP		0.34
Mutation Taster		=52/48	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs200935246; hg19: chr2-50280526;