chr2-50504180-G-A

Variant names:

• chr2-50504180-G-A
• rs6754640
• NM_001330078.2:c.2497+2315C>T

Variant summary

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

The NM_001330078.2(NRXN1):​c.2497+2315C>T 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 147,444 control chromosomes in the GnomAD database, including 13,500 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 (13500 hom., cov: 27)
• Consequence: NRXN1 NM_001330078.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.136
• Publications: 3 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=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.49 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRXN1	NM_001330078.2	c.2497+2315C>T		intron_variant	Intron 13 of 22	ENST00000401669.7	NP_001317007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NRXN1	ENST00000401669.7	c.2497+2315C>T		intron_variant	Intron 13 of 22	5	NM_001330078.2	ENSP00000385017.2

Frequencies

GnomAD3 genomes AF: 0.417 AC: 61416 AN: 147376 Hom.: 13482 Cov.: 27

Gnomad AFR AF: 0.496

Gnomad AMI AF: 0.467

Gnomad AMR AF: 0.313

Gnomad ASJ AF: 0.493

Gnomad EAS AF: 0.0923

Gnomad SAS AF: 0.387

Gnomad FIN AF: 0.469

Gnomad MID AF: 0.537

Gnomad NFE AF: 0.407

Gnomad OTH AF: 0.418

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

GnomAD4 genome AF: 0.417 AC: 61464 AN: 147444 Hom.: 13500 Cov.: 27 AF XY: 0.415 AC XY: 29690 AN XY: 71592

African (AFR) AF: 0.496 AC: 19655 AN: 39624

American (AMR) AF: 0.313 AC: 4635 AN: 14822

Ashkenazi Jewish (ASJ) AF: 0.493 AC: 1700 AN: 3450

East Asian (EAS) AF: 0.0920 AC: 460 AN: 5000

South Asian (SAS) AF: 0.387 AC: 1817 AN: 4690

European-Finnish (FIN) AF: 0.469 AC: 4340 AN: 9260

Middle Eastern (MID) AF: 0.544 AC: 148 AN: 272

European-Non Finnish (NFE) AF: 0.407 AC: 27431 AN: 67362

Other (OTH) AF: 0.415 AC: 854 AN: 2056

Alfa AF: 0.399 Hom.: 25277

Bravo AF: 0.400

Asia WGS AF: 0.268 AC: 933 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	2.1
DANN	Benign	0.44
PhyloP100		0.14
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: rs6754640; hg19: chr2-50731318;