rs777054372

Variant names:

• chr2-50346867-C-A
• rs777054372
• ENST00000342183.9:c.83G>T

Your query was ambiguous. Multiple possible variants found:

• chr2-50346867-C-A
• chr2-50346867-C-G
• chr2-50346867-C-T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_001330092.2(NRXN1):​c.83G>T​(p.Gly28Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000295 in 1,391,486 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict 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. G28A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000032 (0 hom.)
• Consequence: NRXN1 NM_001330092.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.03
• Publications: 0 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: Ambry Genetics, G2P, 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 -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.38637918).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001330092.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRXN1	NM_001330078.2	MANE Select	c.3365-109897G>T		intron	N/A	NP_001317007.1	Q9ULB1-5
	NRXN1	NM_001330092.2		c.83G>T	p.Gly28Val	missense	Exon 1 of 7	NP_001317021.1	P58400-2
	NRXN1	NM_001330091.2		c.83G>T	p.Gly28Val	missense	Exon 1 of 7	NP_001317020.1	A0A0D9SEM5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRXN1	ENST00000342183.9	TSL:1	c.83G>T	p.Gly28Val	missense	Exon 1 of 6	ENSP00000341184.5	P58400-1
	NRXN1	ENST00000401669.7	TSL:5 MANE Select	c.3365-109897G>T		intron	N/A	ENSP00000385017.2	Q9ULB1-5
	NRXN1	ENST00000404971.5	TSL:1	c.3485-109897G>T		intron	N/A	ENSP00000385142.1	Q9ULB1-3

Frequencies

GnomAD3 genomes AF: 0.00000663 AC: 1 AN: 150816 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000322 AC: 40 AN: 1240670 Hom.: 0 Cov.: 30 AF XY: 0.0000346 AC XY: 21 AN XY: 607734

African (AFR) AF: 0.00 AC: 0 AN: 26170

American (AMR) AF: 0.00 AC: 0 AN: 17578

Ashkenazi Jewish (ASJ) AF: 0.0000499 AC: 1 AN: 20022

East Asian (EAS) AF: 0.00 AC: 0 AN: 28618

South Asian (SAS) AF: 0.0000211 AC: 1 AN: 47474

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40712

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4114

European-Non Finnish (NFE) AF: 0.0000378 AC: 38 AN: 1005604

Other (OTH) AF: 0.00 AC: 0 AN: 50378

GnomAD4 genome AF: 0.00000663 AC: 1 AN: 150816 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 73614

African (AFR) AF: 0.00 AC: 0 AN: 41206

American (AMR) AF: 0.00 AC: 0 AN: 15152

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3456

East Asian (EAS) AF: 0.00 AC: 0 AN: 5122

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10144

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67608

Other (OTH) AF: 0.00 AC: 0 AN: 2074

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.012	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	T
Eigen	Benign	0.088
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.46	T
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		4.0
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.13
Sift	Benign	0.16	T
Sift4G	Benign	0.15	T
Polyphen		0.73	P
Vest4		0.62
MutPred		0.36		Loss of disorder (P = 0.021)
MVP		0.15
ClinPred		0.47	T
GERP RS		5.0
Mutation Taster		=74/26	polymorphism

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

Other links and lift over

dbSNP: rs777054372; hg19: chr2-50574005;