2-50346870-GCGCCGCCGCCGCCGCCGCCGC-GCGCCGCCGCCGCCGC

Variant names:

• chr2-50346870-GCGCCGC-G
• rs750165040
• ENST00000342183.9:c.74_79delGCGGCG

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.74_79delGCGGCG​(p.Gly25_Gly26del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00012 in 1,366,588 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (1 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-GCGCCGC-G is Benign according to our data. Variant chr2-50346870-GCGCCGC-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1220637.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.3365-109906_3365-109901delGCGGCG		intron	N/A	NP_001317007.1
	NRXN1	NM_001330092.2		c.74_79delGCGGCG	p.Gly25_Gly26del	disruptive_inframe_deletion	Exon 1 of 7	NP_001317021.1
	NRXN1	NM_001330091.2		c.74_79delGCGGCG	p.Gly25_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.74_79delGCGGCG	p.Gly25_Gly26del	disruptive_inframe_deletion	Exon 1 of 6	ENSP00000341184.5
	NRXN1	ENST00000401669.7	TSL:5 MANE Select	c.3365-109906_3365-109901delGCGGCG		intron	N/A	ENSP00000385017.2
	NRXN1	ENST00000404971.5	TSL:1	c.3485-109906_3485-109901delGCGGCG		intron	N/A	ENSP00000385142.1

Frequencies

GnomAD3 genomes AF: 0.000133 AC: 20 AN: 150380 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000148

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000118 AC: 144 AN: 1216208 Hom.: 1 AF XY: 0.000126 AC XY: 75 AN XY: 594938

African (AFR) AF: 0.000157 AC: 4 AN: 25488

American (AMR) AF: 0.00 AC: 0 AN: 15590

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19414

East Asian (EAS) AF: 0.00 AC: 0 AN: 28038

South Asian (SAS) AF: 0.000135 AC: 6 AN: 44604

European-Finnish (FIN) AF: 0.0000256 AC: 1 AN: 39130

Middle Eastern (MID) AF: 0.000254 AC: 1 AN: 3942

European-Non Finnish (NFE) AF: 0.000126 AC: 125 AN: 990700

Other (OTH) AF: 0.000142 AC: 7 AN: 49302

GnomAD4 genome AF: 0.000133 AC: 20 AN: 150380 Hom.: 0 Cov.: 32 AF XY: 0.000136 AC XY: 10 AN XY: 73358

African (AFR) AF: 0.000243 AC: 10 AN: 41184

American (AMR) AF: 0.00 AC: 0 AN: 15098

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5094

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10016

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

European-Non Finnish (NFE) AF: 0.000148 AC: 10 AN: 67428

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		=184/16	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;