2-50367024-T-C

Variant names:

• chr2-50367024-T-C
• rs4377361
• NM_001330078.2:c.3364+98418A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001330078.2(NRXN1):​c.3364+98418A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.417 in 151,838 control chromosomes in the GnomAD database, including 13,457 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.42 (13457 hom., cov: 32)
• Consequence: NRXN1 NM_001330078.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.06
• Publications: 1 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.55 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRXN1	NM_001330078.2	c.3364+98418A>G		intron_variant	Intron 17 of 22	ENST00000401669.7	NP_001317007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NRXN1	ENST00000401669.7	c.3364+98418A>G		intron_variant	Intron 17 of 22	5	NM_001330078.2	ENSP00000385017.2

Frequencies

GnomAD3 genomes AF: 0.417 AC: 63285 AN: 151716 Hom.: 13439 Cov.: 32

Gnomad AFR AF: 0.465

Gnomad AMI AF: 0.349

Gnomad AMR AF: 0.395

Gnomad ASJ AF: 0.319

Gnomad EAS AF: 0.567

Gnomad SAS AF: 0.352

Gnomad FIN AF: 0.409

Gnomad MID AF: 0.346

Gnomad NFE AF: 0.393

Gnomad OTH AF: 0.433

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.417 AC: 63348 AN: 151838 Hom.: 13457 Cov.: 32 AF XY: 0.416 AC XY: 30898 AN XY: 74196

African (AFR) AF: 0.465 AC: 19259 AN: 41434

American (AMR) AF: 0.395 AC: 6006 AN: 15208

Ashkenazi Jewish (ASJ) AF: 0.319 AC: 1105 AN: 3464

East Asian (EAS) AF: 0.567 AC: 2919 AN: 5150

South Asian (SAS) AF: 0.352 AC: 1695 AN: 4822

European-Finnish (FIN) AF: 0.409 AC: 4327 AN: 10568

Middle Eastern (MID) AF: 0.349 AC: 102 AN: 292

European-Non Finnish (NFE) AF: 0.393 AC: 26691 AN: 67878

Other (OTH) AF: 0.438 AC: 926 AN: 2112

Alfa AF: 0.397 Hom.: 50910

Bravo AF: 0.419

Asia WGS AF: 0.477 AC: 1657 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.73
DANN	Benign	0.26
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs4377361; hg19: chr2-50594162;