rs79970751

Variant names:

• chr2-50053466-T-C
• rs79970751
• NM_001330078.2:c.3933A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001330078.2(NRXN1):​c.3933A>G​(p.Ala1311Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00666 in 1,614,012 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0049 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0068 (49 hom.)
• Consequence: NRXN1 NM_001330078.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.957
• Publications: 4 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: Ambry Genetics, G2P, 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 2-50053466-T-C is Benign according to our data. Variant chr2-50053466-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93602.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.957 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00493 (751/152290) while in subpopulation AMR AF = 0.00883 (135/15294). AF 95% confidence interval is 0.00761. There are 6 homozygotes in GnomAd4. There are 349 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR,AD,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001330078.2. 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.3933A>G	p.Ala1311Ala	synonymous	Exon 21 of 23	NP_001317007.1	Q9ULB1-5
	NRXN1	NM_001135659.3		c.4053A>G	p.Ala1351Ala	synonymous	Exon 22 of 24	NP_001129131.1	Q9ULB1-3
	NRXN1	NM_001330093.2		c.3930A>G	p.Ala1310Ala	synonymous	Exon 21 of 23	NP_001317022.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRXN1	ENST00000401669.7	TSL:5 MANE Select	c.3933A>G	p.Ala1311Ala	synonymous	Exon 21 of 23	ENSP00000385017.2	Q9ULB1-5
	NRXN1	ENST00000404971.5	TSL:1	c.4053A>G	p.Ala1351Ala	synonymous	Exon 22 of 24	ENSP00000385142.1	Q9ULB1-3
	NRXN1	ENST00000625672.2	TSL:1	c.3909A>G	p.Ala1303Ala	synonymous	Exon 19 of 21	ENSP00000485887.1	Q9ULB1-2

Frequencies

GnomAD3 genomes AF: 0.00494 AC: 751 AN: 152172 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00154

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.00884

Gnomad ASJ AF: 0.00836

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000847

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00695

Gnomad OTH AF: 0.00525

GnomAD2 exomes AF: 0.00400 AC: 1005 AN: 251110 AF XY: 0.00403

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00324

Gnomad ASJ exome AF: 0.00764

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000601

Gnomad NFE exome AF: 0.00642

Gnomad OTH exome AF: 0.00637

GnomAD4 exome AF: 0.00684 AC: 9993 AN: 1461722 Hom.: 49 Cov.: 32 AF XY: 0.00665 AC XY: 4839 AN XY: 727154

African (AFR) AF: 0.00143 AC: 48 AN: 33468

American (AMR) AF: 0.00315 AC: 141 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00696 AC: 182 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.000765 AC: 66 AN: 86256

European-Finnish (FIN) AF: 0.000674 AC: 36 AN: 53392

Middle Eastern (MID) AF: 0.0125 AC: 72 AN: 5768

European-Non Finnish (NFE) AF: 0.00811 AC: 9022 AN: 1111918

Other (OTH) AF: 0.00704 AC: 425 AN: 60390

GnomAD4 genome AF: 0.00493 AC: 751 AN: 152290 Hom.: 6 Cov.: 33 AF XY: 0.00469 AC XY: 349 AN XY: 74474

African (AFR) AF: 0.00154 AC: 64 AN: 41568

American (AMR) AF: 0.00883 AC: 135 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00836 AC: 29 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4830

European-Finnish (FIN) AF: 0.000847 AC: 9 AN: 10626

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00695 AC: 473 AN: 68012

Other (OTH) AF: 0.00520 AC: 11 AN: 2116

Alfa AF: 0.00585 Hom.: 2

Bravo AF: 0.00498

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00753

EpiControl AF: 0.00747

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	3	not specified (3)
-	-	2	Pitt-Hopkins-like syndrome 2 (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	NRXN1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	8.0
DANN	Benign	0.65
PhyloP100		0.96
Mutation Taster		=83/17	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: rs79970751; hg19: chr2-50280604;