2-50346870-GCGCCGCCGCCGCCGCCGCCGC-GCGCCGCCGCCGCCGCCGCCGCCGCCGC

Variant names:

• chr2-50346870-G-GCGCCGC
• rs750165040
• ENST00000342183.9:c.74_79dupGCGGCG

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP3 BP6_Very_Strong BS1

The ENST00000342183.9(NRXN1):​c.74_79dupGCGGCG​(p.Gly25_Gly26dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0016 in 1,366,670 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A27A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (0 hom.)
• Consequence: NRXN1 ENST00000342183.9 conservative_inframe_insertion
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.48
• Publications: 0 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 -13 ACMG points.

• BP3: Nonframeshift variant in repetitive region in ENST00000342183.9
• BP6: Variant 2-50346870-G-GCGCCGC is Benign according to our data. Variant chr2-50346870-G-GCGCCGC is described in ClinVar as Likely_benign. ClinVar VariationId is 516945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00137 (206/150482) while in subpopulation NFE AF = 0.00197 (133/67418). AF 95% confidence interval is 0.0017. There are 0 homozygotes in GnomAd4. There are 95 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRXN1	NM_001330078.2	c.3365-109906_3365-109901dupGCGGCG		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.3365-109906_3365-109901dupGCGGCG		intron_variant	Intron 17 of 22	5	NM_001330078.2	ENSP00000385017.2

Frequencies

GnomAD3 genomes AF: 0.00137 AC: 206 AN: 150382 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000631

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00132

Gnomad ASJ AF: 0.00551

Gnomad EAS AF: 0.000589

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.0000998

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00197

Gnomad OTH AF: 0.000965

GnomAD2 exomes AF: 0.000160 AC: 12 AN: 74950 AF XY: 0.000158

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000166

Gnomad ASJ exome AF: 0.000202

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000290

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00163 AC: 1986 AN: 1216188 Hom.: 0 Cov.: 30 AF XY: 0.00158 AC XY: 939 AN XY: 594922

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000432 AC: 11 AN: 25488

American (AMR) AF: 0.000192 AC: 3 AN: 15588

Ashkenazi Jewish (ASJ) AF: 0.00211 AC: 41 AN: 19410

East Asian (EAS) AF: 0.0000357 AC: 1 AN: 28040

South Asian (SAS) AF: 0.0000224 AC: 1 AN: 44628

European-Finnish (FIN) AF: 0.000102 AC: 4 AN: 39152

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3942

European-Non Finnish (NFE) AF: 0.00189 AC: 1875 AN: 990648

Other (OTH) AF: 0.00101 AC: 50 AN: 49292

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00137 AC: 206 AN: 150482 Hom.: 0 Cov.: 32 AF XY: 0.00129 AC XY: 95 AN XY: 73468

African (AFR) AF: 0.000654 AC: 27 AN: 41302

American (AMR) AF: 0.00132 AC: 20 AN: 15118

Ashkenazi Jewish (ASJ) AF: 0.00551 AC: 19 AN: 3448

East Asian (EAS) AF: 0.000394 AC: 2 AN: 5078

South Asian (SAS) AF: 0.000416 AC: 2 AN: 4806

European-Finnish (FIN) AF: 0.0000998 AC: 1 AN: 10018

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00197 AC: 133 AN: 67418

Other (OTH) AF: 0.000957 AC: 2 AN: 2090

Alfa AF: 0.000111 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Jan 17, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Inborn genetic diseases Benign:1

Jun 12, 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

Jul 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NRXN1: BP3 -

Pitt-Hopkins-like syndrome 2;C3808494:Chromosome 2p16.3 deletion syndrome Benign:1

May 16, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.5
Mutation Taster		=79/21	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs750165040; hg19: chr2-50574008;