chr2-50621200-T-A

Variant names:

• chr2-50621200-T-A
• rs201802152
• NM_001330078.2:c.1158+26A>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_001135659.3(NRXN1):​c.1278+5A>T variant causes a splice region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000915 in 1,554,320 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00074 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00093 (4 hom.)
• Consequence: NRXN1 NM_001135659.3 splice_region, intron
• Scores: Splicing: ADA: 0.001757
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:10
• Conservation: PhyloP100: 8.01
• Publications: 2 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)

ENSG00000283058 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 2-50621200-T-A is Benign according to our data. Variant chr2-50621200-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 129818.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000736 (112/152216) while in subpopulation SAS AF = 0.0029 (14/4828). AF 95% confidence interval is 0.00175. There are 0 homozygotes in GnomAd4. There are 66 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR,AD,Unknown gene

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.1158+26A>T		intron	N/A	NP_001317007.1
	NRXN1	NM_001135659.3		c.1278+5A>T		splice_region intron	N/A	NP_001129131.1
	NRXN1	NM_001330093.2		c.1155+26A>T		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.1158+26A>T		intron	N/A	ENSP00000385017.2
	NRXN1	ENST00000404971.5	TSL:1	c.1278+5A>T		splice_region intron	N/A	ENSP00000385142.1
	NRXN1	ENST00000625672.2	TSL:1	c.1135-1017A>T		intron	N/A	ENSP00000485887.1

Frequencies

GnomAD3 genomes AF: 0.000736 AC: 112 AN: 152098 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00207

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000970

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00112 AC: 195 AN: 173744 AF XY: 0.00137

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000276

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00129

Gnomad NFE exome AF: 0.00108

Gnomad OTH exome AF: 0.000854

GnomAD4 exome AF: 0.000934 AC: 1310 AN: 1402104 Hom.: 4 Cov.: 28 AF XY: 0.00106 AC XY: 731 AN XY: 692540

African (AFR) AF: 0.0000625 AC: 2 AN: 31980

American (AMR) AF: 0.000275 AC: 10 AN: 36306

Ashkenazi Jewish (ASJ) AF: 0.0000399 AC: 1 AN: 25058

East Asian (EAS) AF: 0.00 AC: 0 AN: 36940

South Asian (SAS) AF: 0.00423 AC: 333 AN: 78734

European-Finnish (FIN) AF: 0.00131 AC: 66 AN: 50274

Middle Eastern (MID) AF: 0.00370 AC: 21 AN: 5680

European-Non Finnish (NFE) AF: 0.000756 AC: 816 AN: 1078844

Other (OTH) AF: 0.00105 AC: 61 AN: 58288

GnomAD4 genome AF: 0.000736 AC: 112 AN: 152216 Hom.: 0 Cov.: 32 AF XY: 0.000887 AC XY: 66 AN XY: 74428

African (AFR) AF: 0.000120 AC: 5 AN: 41542

American (AMR) AF: 0.000262 AC: 4 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4828

European-Finnish (FIN) AF: 0.00207 AC: 22 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000970 AC: 66 AN: 68018

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000751 Hom.: 0

Bravo AF: 0.000616

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	22
DANN	Benign	0.90
PhyloP100		8.0
Mutation Taster		=46/54	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0018
dbscSNV1_RF	Benign	0.14
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: rs201802152; hg19: chr2-50848338;