rs7571753

Positions:

• chr2-50506820-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001330078.2(NRXN1):​c.2375-203A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.364 in 542,316 control chromosomes in the GnomAD database, including 38,971 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (9911 hom., cov: 30)
  • Exomes 𝑓: 0.37 (29060 hom.)
• Consequence: NRXN1 NM_001330078.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0910

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 2-50506820-T-C is Benign according to our data. Variant chr2-50506820-T-C is described in ClinVar as [Benign]. Clinvar id is 667703.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.398 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NRXN1	NM_001330078.2	c.2375-203A>G		intron_variant		ENST00000401669.7	NP_001317007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NRXN1	ENST00000401669.7	c.2375-203A>G		intron_variant		5	NM_001330078.2	ENSP00000385017	A1

Frequencies

GnomAD3 genomes AF: 0.348 AC: 52832 AN: 151706 Hom.: 9916 Cov.: 30

Gnomad AFR AF: 0.268

Gnomad AMI AF: 0.467

Gnomad AMR AF: 0.284

Gnomad ASJ AF: 0.476

Gnomad EAS AF: 0.0947

Gnomad SAS AF: 0.388

Gnomad FIN AF: 0.458

Gnomad MID AF: 0.532

Gnomad NFE AF: 0.402

Gnomad OTH AF: 0.358

GnomAD4 exome AF: 0.370 AC: 144578 AN: 390492 Hom.: 29060 Cov.: 4 AF XY: 0.373 AC XY: 75725 AN XY: 202916

Gnomad4 AFR exome AF: 0.271

Gnomad4 AMR exome AF: 0.238

Gnomad4 ASJ exome AF: 0.467

Gnomad4 EAS exome AF: 0.0794

Gnomad4 SAS exome AF: 0.395

Gnomad4 FIN exome AF: 0.439

Gnomad4 NFE exome AF: 0.403

Gnomad4 OTH exome AF: 0.372

GnomAD4 genome AF: 0.348 AC: 52830 AN: 151824 Hom.: 9911 Cov.: 30 AF XY: 0.348 AC XY: 25810 AN XY: 74206

Gnomad4 AFR AF: 0.267

Gnomad4 AMR AF: 0.284

Gnomad4 ASJ AF: 0.476

Gnomad4 EAS AF: 0.0941

Gnomad4 SAS AF: 0.388

Gnomad4 FIN AF: 0.458

Gnomad4 NFE AF: 0.402

Gnomad4 OTH AF: 0.355

Alfa AF: 0.370 Hom.: 1731

Bravo AF: 0.324

Asia WGS AF: 0.253 AC: 880 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	14
DANN	Benign	0.70

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

Other links and lift over

dbSNP: rs7571753; hg19: chr2-50733958; COSMIC: COSV58459570;