2-50346870-GCGCCGCCGCCGCCGCCGC-GCGCCGCCGC

Position:

• chr2-50346870-GCGCCGCCGCCGCCGCCGC-GCGCCGCCGC

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The ENST00000342183.9(NRXN1):​c.71_79del​(p.Gly24_Gly26del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.000902 in 1,366,786 control chromosomes in the GnomAD database, including 37 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00066 (37 hom.)
• Consequence: NRXN1 ENST00000342183.9 inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.96

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 -16 ACMG points.

• BP6: Variant 2-50346870-GCGCCGCCGC-G is Benign according to our data. Variant chr2-50346870-GCGCCGCCGC-G is described in ClinVar as [Likely_benign]. Clinvar id is 281242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-50346870-GCGCCGCCGC-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00282 (425/150480) while in subpopulation AFR AF= 0.00855 (353/41300). AF 95% confidence interval is 0.00781. There are 0 homozygotes in gnomad4. There are 206 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 37 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NRXN1	NM_001330078.2	c.3365-109909_3365-109901del		intron_variant		ENST00000401669.7	NP_001317007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NRXN1	ENST00000401669.7	c.3365-109909_3365-109901del		intron_variant		5	NM_001330078.2	ENSP00000385017	A1

Frequencies

GnomAD3 genomes AF: 0.00280 AC: 421 AN: 150380 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00847

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00232

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000393

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000341

Gnomad OTH AF: 0.00145

GnomAD3 exomes AF: 0.00148 AC: 111 AN: 74950 Hom.: 11 AF XY: 0.00160 AC XY: 71 AN XY: 44242

Gnomad AFR exome AF: 0.00305

Gnomad AMR exome AF: 0.00646

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00466

Gnomad SAS exome AF: 0.00364

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000290

Gnomad OTH exome AF: 0.00108

GnomAD4 exome AF: 0.000664 AC: 808 AN: 1216306 Hom.: 37 AF XY: 0.000748 AC XY: 445 AN XY: 594994

Gnomad4 AFR exome AF: 0.00808

Gnomad4 AMR exome AF: 0.00436

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00136

Gnomad4 SAS exome AF: 0.00531

Gnomad4 FIN exome AF: 0.0000255

Gnomad4 NFE exome AF: 0.000208

Gnomad4 OTH exome AF: 0.00101

GnomAD4 genome AF: 0.00282 AC: 425 AN: 150480 Hom.: 0 Cov.: 32 AF XY: 0.00280 AC XY: 206 AN XY: 73466

Gnomad4 AFR AF: 0.00855

Gnomad4 AMR AF: 0.00232

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000394

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000341

Gnomad4 OTH AF: 0.00144

Bravo AF: 0.00306

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	NRXN1: BS2 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 11, 2017

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 20, 2017

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

NRXN1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 14, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs750165040; hg19: chr2-50574008;