2-50441622-T-G

Variant names:

• chr2-50441622-T-G
• rs10048731
• NM_001330078.2:c.3364+23820A>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BS1 BS2

The NM_001330078.2(NRXN1):​c.3364+23820A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00396 in 152,066 control chromosomes in the GnomAD database, including 2 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 0.0040 (2 hom., cov: 32)
• Consequence: NRXN1 NM_001330078.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0770
• Publications: 3 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00396 (602/152066) while in subpopulation NFE AF = 0.00716 (487/67970). AF 95% confidence interval is 0.00664. There are 2 homozygotes in GnomAd4. There are 253 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRXN1	NM_001330078.2	MANE Select	c.3364+23820A>C		intron	N/A	NP_001317007.1
	NRXN1	NM_001135659.3		c.3484+23820A>C		intron	N/A	NP_001129131.1
	NRXN1	NM_001330093.2		c.3361+23820A>C		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.3364+23820A>C		intron	N/A	ENSP00000385017.2
	NRXN1	ENST00000404971.5	TSL:1	c.3484+23820A>C		intron	N/A	ENSP00000385142.1
	NRXN1	ENST00000625672.2	TSL:1	c.3340+23820A>C		intron	N/A	ENSP00000485887.1

Frequencies

GnomAD3 genomes AF: 0.00396 AC: 602 AN: 151948 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.000758

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00716

Gnomad OTH AF: 0.00287

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

GnomAD4 genome AF: 0.00396 AC: 602 AN: 152066 Hom.: 2 Cov.: 32 AF XY: 0.00340 AC XY: 253 AN XY: 74328

African (AFR) AF: 0.00106 AC: 44 AN: 41502

American (AMR) AF: 0.00203 AC: 31 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5154

South Asian (SAS) AF: 0.00394 AC: 19 AN: 4828

European-Finnish (FIN) AF: 0.000758 AC: 8 AN: 10558

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

European-Non Finnish (NFE) AF: 0.00716 AC: 487 AN: 67970

Other (OTH) AF: 0.00284 AC: 6 AN: 2110

Alfa AF: 0.0000139 Hom.: 26298

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	9.6
DANN	Benign	0.80
PhyloP100		0.077

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: rs10048731; hg19: chr2-50668760;