2-50134250-C-T

Variant names:

• chr2-50134250-C-T
• rs6545153
• NM_001330078.2:c.3547-42756G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001330078.2(NRXN1):​c.3547-42756G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.331 in 138,016 control chromosomes in the GnomAD database, including 7,540 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.33 (7540 hom., cov: 24)
• Consequence: NRXN1 NM_001330078.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.28
• 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: 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.369 is higher than 0.05.

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.3547-42756G>A		intron	N/A	NP_001317007.1	Q9ULB1-5
	NRXN1	NM_001135659.3		c.3667-42756G>A		intron	N/A	NP_001129131.1	Q9ULB1-3
	NRXN1	NM_001330093.2		c.3544-42756G>A		intron	N/A	NP_001317022.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRXN1	ENST00000401669.7	TSL:5 MANE Select	c.3547-42756G>A		intron	N/A	ENSP00000385017.2	Q9ULB1-5
	NRXN1	ENST00000404971.5	TSL:1	c.3667-42756G>A		intron	N/A	ENSP00000385142.1	Q9ULB1-3
	NRXN1	ENST00000625672.2	TSL:1	c.3523-42756G>A		intron	N/A	ENSP00000485887.1	Q9ULB1-2

Frequencies

GnomAD3 genomes AF: 0.331 AC: 45693 AN: 137942 Hom.: 7545 Cov.: 24

Gnomad AFR AF: 0.264

Gnomad AMI AF: 0.359

Gnomad AMR AF: 0.281

Gnomad ASJ AF: 0.329

Gnomad EAS AF: 0.251

Gnomad SAS AF: 0.290

Gnomad FIN AF: 0.430

Gnomad MID AF: 0.372

Gnomad NFE AF: 0.373

Gnomad OTH AF: 0.330

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.331 AC: 45694 AN: 138016 Hom.: 7540 Cov.: 24 AF XY: 0.327 AC XY: 21829 AN XY: 66660

African (AFR) AF: 0.264 AC: 9609 AN: 36440

American (AMR) AF: 0.281 AC: 3590 AN: 12766

Ashkenazi Jewish (ASJ) AF: 0.329 AC: 1096 AN: 3332

East Asian (EAS) AF: 0.252 AC: 1136 AN: 4514

South Asian (SAS) AF: 0.290 AC: 1243 AN: 4282

European-Finnish (FIN) AF: 0.430 AC: 3775 AN: 8780

Middle Eastern (MID) AF: 0.377 AC: 101 AN: 268

European-Non Finnish (NFE) AF: 0.373 AC: 24218 AN: 64898

Other (OTH) AF: 0.329 AC: 622 AN: 1890

Alfa AF: 0.341 Hom.: 24813

Bravo AF: 0.298

Asia WGS AF: 0.282 AC: 978 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.58
DANN	Benign	0.21
PhyloP100		-1.3
Mutation Taster		=99/1	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: rs6545153; hg19: chr2-50361388;