chr2-50346870-GCGC-G

Variant names:

• chr2-50346870-GCGC-G
• rs750165040
• ENST00000342183.9:c.77_79delGCG

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS1

The NM_001330092.2(NRXN1):​c.77_79delGCG​(p.Gly26del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.000722 in 1,354,980 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00080 (0 hom.)
• Consequence: NRXN1 NM_001330092.2 disruptive_inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• 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 -12 ACMG points.

• BP6: Variant 2-50346870-GCGC-G is Benign according to our data. Variant chr2-50346870-GCGC-G is described in ClinVar as [Likely_benign]. Clinvar id is 588566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.000799 (963/1204616) while in subpopulation SAS AF= 0.00395 (174/44032). AF 95% confidence interval is 0.00347. There are 0 homozygotes in gnomad4_exome. There are 524 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRXN1	NM_001330078.2	c.3365-109903_3365-109901delGCG		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.3365-109903_3365-109901delGCG		intron_variant	Intron 17 of 22	5	NM_001330078.2	ENSP00000385017.2

Frequencies

GnomAD3 genomes AF: 0.0000998 AC: 15 AN: 150364 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000662

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000589

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000890

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000907 AC: 68 AN: 74950 Hom.: 0 AF XY: 0.000769 AC XY: 34 AN XY: 44242

Gnomad AFR exome AF: 0.00102

Gnomad AMR exome AF: 0.00116

Gnomad ASJ exome AF: 0.000606

Gnomad EAS exome AF: 0.00140

Gnomad SAS exome AF: 0.000331

Gnomad FIN exome AF: 0.00219

Gnomad NFE exome AF: 0.000609

Gnomad OTH exome AF: 0.00162

GnomAD4 exome AF: 0.000799 AC: 963 AN: 1204616 Hom.: 0 AF XY: 0.000890 AC XY: 524 AN XY: 588858

Gnomad4 AFR exome AF: 0.000630

Gnomad4 AMR exome AF: 0.00142

Gnomad4 ASJ exome AF: 0.00125

Gnomad4 EAS exome AF: 0.00111

Gnomad4 SAS exome AF: 0.00395

Gnomad4 FIN exome AF: 0.00236

Gnomad4 NFE exome AF: 0.000567

Gnomad4 OTH exome AF: 0.000841

GnomAD4 genome AF: 0.0000998 AC: 15 AN: 150364 Hom.: 0 Cov.: 32 AF XY: 0.0000682 AC XY: 5 AN XY: 73352

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.0000662

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000589

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000890

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Benign:1

Sep 16, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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. -

not provided Benign:1

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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: rs750165040; hg19: chr2-50574008;