rs7571753

Variant names:

• chr2-50506820-T-C
• rs7571753
• NM_001330078.2:c.2375-203A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001135659.3(NRXN1):​c.2495-203A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.364 in 542,316 control chromosomes in the GnomAD database, including 38,971 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (9911 hom., cov: 30)
  • Exomes 𝑓: 0.37 (29060 hom.)
• Consequence: NRXN1 NM_001135659.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0910
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 2-50506820-T-C is Benign according to our data. Variant chr2-50506820-T-C is described in ClinVar as Benign. ClinVar VariationId is 667703.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.398 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001135659.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRXN1	NM_001330078.2	MANE Select	c.2375-203A>G		intron	N/A	NP_001317007.1
	NRXN1	NM_001135659.3		c.2495-203A>G		intron	N/A	NP_001129131.1
	NRXN1	NM_001330093.2		c.2372-203A>G		intron	N/A	NP_001317022.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRXN1	ENST00000401669.7	TSL:5 MANE Select	c.2375-203A>G		intron	N/A	ENSP00000385017.2
	NRXN1	ENST00000404971.5	TSL:1	c.2495-203A>G		intron	N/A	ENSP00000385142.1
	NRXN1	ENST00000625672.2	TSL:1	c.2351-203A>G		intron	N/A	ENSP00000485887.1

Frequencies

GnomAD3 genomes AF: 0.348 AC: 52832 AN: 151706 Hom.: 9916 Cov.: 30

Gnomad AFR AF: 0.268

Gnomad AMI AF: 0.467

Gnomad AMR AF: 0.284

Gnomad ASJ AF: 0.476

Gnomad EAS AF: 0.0947

Gnomad SAS AF: 0.388

Gnomad FIN AF: 0.458

Gnomad MID AF: 0.532

Gnomad NFE AF: 0.402

Gnomad OTH AF: 0.358

GnomAD4 exome AF: 0.370 AC: 144578 AN: 390492 Hom.: 29060 Cov.: 4 AF XY: 0.373 AC XY: 75725 AN XY: 202916

African (AFR) AF: 0.271 AC: 3098 AN: 11442

American (AMR) AF: 0.238 AC: 3885 AN: 16302

Ashkenazi Jewish (ASJ) AF: 0.467 AC: 5615 AN: 12034

East Asian (EAS) AF: 0.0794 AC: 2318 AN: 29178

South Asian (SAS) AF: 0.395 AC: 12928 AN: 32738

European-Finnish (FIN) AF: 0.439 AC: 12060 AN: 27466

Middle Eastern (MID) AF: 0.477 AC: 850 AN: 1782

European-Non Finnish (NFE) AF: 0.403 AC: 95201 AN: 236376

Other (OTH) AF: 0.372 AC: 8623 AN: 23174

GnomAD4 genome AF: 0.348 AC: 52830 AN: 151824 Hom.: 9911 Cov.: 30 AF XY: 0.348 AC XY: 25810 AN XY: 74206

African (AFR) AF: 0.267 AC: 11070 AN: 41394

American (AMR) AF: 0.284 AC: 4323 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.476 AC: 1652 AN: 3470

East Asian (EAS) AF: 0.0941 AC: 485 AN: 5154

South Asian (SAS) AF: 0.388 AC: 1861 AN: 4798

European-Finnish (FIN) AF: 0.458 AC: 4829 AN: 10552

Middle Eastern (MID) AF: 0.531 AC: 156 AN: 294

European-Non Finnish (NFE) AF: 0.402 AC: 27284 AN: 67910

Other (OTH) AF: 0.355 AC: 746 AN: 2102

Alfa AF: 0.367 Hom.: 1759

Bravo AF: 0.324

Asia WGS AF: 0.253 AC: 880 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	14
DANN	Benign	0.70
PhyloP100		-0.091
Mutation Taster		=100/0	polymorphism (auto)

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: rs7571753; hg19: chr2-50733958; COSMIC: COSV58459570;