2-50346870-GCGCCGCCGCCGCCGCCGCCGC-GCGCCGCCGCCGCCGCCGC

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP3 BP6_Very_Strong

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 (★★). Synonymous variant affecting the same amino acid position (i.e. G26G) has been classified 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
• 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 -9 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001330092.2
• BP6: Variant 2-50346870-GCGC-G is Benign according to our data. Variant chr2-50346870-GCGC-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 588566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001330092.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRXN1	NM_001330078.2	MANE Select	c.3365-109903_3365-109901delGCG		intron	N/A	NP_001317007.1
	NRXN1	NM_001330092.2		c.77_79delGCG	p.Gly26del	disruptive_inframe_deletion	Exon 1 of 7	NP_001317021.1
	NRXN1	NM_001330091.2		c.77_79delGCG	p.Gly26del	disruptive_inframe_deletion	Exon 1 of 7	NP_001317020.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRXN1	ENST00000342183.9	TSL:1	c.77_79delGCG	p.Gly26del	disruptive_inframe_deletion	Exon 1 of 6	ENSP00000341184.5
	NRXN1	ENST00000401669.7	TSL:5 MANE Select	c.3365-109903_3365-109901delGCG		intron	N/A	ENSP00000385017.2
	NRXN1	ENST00000404971.5	TSL:1	c.3485-109903_3485-109901delGCG		intron	N/A	ENSP00000385142.1

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

GnomAD2 exomes AF: 0.000907 AC: 68 AN: 74950 AF XY: 0.000769

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 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

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

African (AFR) AF: 0.000630 AC: 16 AN: 25390

American (AMR) AF: 0.00142 AC: 22 AN: 15450

Ashkenazi Jewish (ASJ) AF: 0.00125 AC: 24 AN: 19172

East Asian (EAS) AF: 0.00111 AC: 31 AN: 27834

South Asian (SAS) AF: 0.00395 AC: 174 AN: 44032

European-Finnish (FIN) AF: 0.00236 AC: 91 AN: 38486

Middle Eastern (MID) AF: 0.00180 AC: 7 AN: 3898

European-Non Finnish (NFE) AF: 0.000567 AC: 557 AN: 981590

Other (OTH) AF: 0.000841 AC: 41 AN: 48764

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.000121 AC: 5 AN: 41184

American (AMR) AF: 0.0000662 AC: 1 AN: 15098

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3448

East Asian (EAS) AF: 0.000589 AC: 3 AN: 5094

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10012

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000890 AC: 6 AN: 67416

Other (OTH) AF: 0.00 AC: 0 AN: 2072

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.0
Mutation Taster		=77/23	polymorphism

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

Other links and lift over

dbSNP: rs750165040; hg19: chr2-50574008; COSMIC: COSV58449887; COSMIC: COSV58449887;