2-49919433-C-G

Position:

• chr2-49919433-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001330078.2(NRXN1):​c.*2511G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.013 in 151,924 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.013 (17 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: NRXN1 NM_001330078.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0890

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 2-49919433-C-G is Benign according to our data. Variant chr2-49919433-C-G is described in ClinVar as [Benign]. Clinvar id is 336505.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.013 (1975/151924) while in subpopulation SAS AF= 0.0436 (210/4818). AF 95% confidence interval is 0.0388. There are 17 homozygotes in gnomad4. There are 986 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 17 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NRXN1	NM_001330078.2	c.*2511G>C		3_prime_UTR_variant	23/23	ENST00000401669.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NRXN1	ENST00000401669.7	c.*2511G>C		3_prime_UTR_variant	23/23	5	NM_001330078.2	A1

Frequencies

GnomAD3 genomes AF: 0.0130 AC: 1974 AN: 151812 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.00312

Gnomad AMI AF: 0.0176

Gnomad AMR AF: 0.0124

Gnomad ASJ AF: 0.00981

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0431

Gnomad FIN AF: 0.0101

Gnomad MID AF: 0.0287

Gnomad NFE AF: 0.0182

Gnomad OTH AF: 0.0216

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

GnomAD4 genome AF: 0.0130 AC: 1975 AN: 151924 Hom.: 17 Cov.: 32 AF XY: 0.0133 AC XY: 986 AN XY: 74232

Gnomad4 AFR AF: 0.00311

Gnomad4 AMR AF: 0.0124

Gnomad4 ASJ AF: 0.00981

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0436

Gnomad4 FIN AF: 0.0101

Gnomad4 NFE AF: 0.0182

Gnomad4 OTH AF: 0.0213

Alfa AF: 0.0140 Hom.: 1

Bravo AF: 0.0116

Asia WGS AF: 0.0160 AC: 57 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Pitt-Hopkins-like syndrome 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.4
DANN	Benign	0.67

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs148938313; hg19: chr2-50146571;