2-50472452-T-G

Variant names:

• chr2-50472452-T-G
• rs201886024
• NM_001330078.2:c.3090A>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS1

The NM_001135659.3(NRXN1):​c.3210A>C​(p.Gly1070Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000153 in 1,611,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: NRXN1 NM_001135659.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 0.373
• Publications: 0 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 2-50472452-T-G is Benign according to our data. Variant chr2-50472452-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 206207.
• BP7: Synonymous conserved (PhyloP=0.373 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000158 (24/152088) while in subpopulation AMR AF = 0.000524 (8/15254). AF 95% confidence interval is 0.000261. There are 0 homozygotes in GnomAd4. There are 14 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.3090A>C	p.Gly1030Gly	synonymous	Exon 16 of 23	NP_001317007.1
	NRXN1	NM_001135659.3		c.3210A>C	p.Gly1070Gly	synonymous	Exon 17 of 24	NP_001129131.1
	NRXN1	NM_001330093.2		c.3087A>C	p.Gly1029Gly	synonymous	Exon 16 of 23	NP_001317022.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRXN1	ENST00000401669.7	TSL:5 MANE Select	c.3090A>C	p.Gly1030Gly	synonymous	Exon 16 of 23	ENSP00000385017.2
	NRXN1	ENST00000404971.5	TSL:1	c.3210A>C	p.Gly1070Gly	synonymous	Exon 17 of 24	ENSP00000385142.1
	NRXN1	ENST00000625672.2	TSL:1	c.3066A>C	p.Gly1022Gly	synonymous	Exon 14 of 21	ENSP00000485887.1

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 151970 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000525

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000959

GnomAD2 exomes AF: 0.000326 AC: 81 AN: 248224 AF XY: 0.000275

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000671

Gnomad ASJ exome AF: 0.00478

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000623

Gnomad OTH exome AF: 0.000499

GnomAD4 exome AF: 0.000153 AC: 223 AN: 1459834 Hom.: 0 Cov.: 31 AF XY: 0.000164 AC XY: 119 AN XY: 726214

African (AFR) AF: 0.0000300 AC: 1 AN: 33344

American (AMR) AF: 0.000673 AC: 30 AN: 44556

Ashkenazi Jewish (ASJ) AF: 0.00499 AC: 130 AN: 26046

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86164

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5756

European-Non Finnish (NFE) AF: 0.0000297 AC: 33 AN: 1110656

Other (OTH) AF: 0.000432 AC: 26 AN: 60254

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152088 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74366

African (AFR) AF: 0.0000241 AC: 1 AN: 41542

American (AMR) AF: 0.000524 AC: 8 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67908

Other (OTH) AF: 0.000949 AC: 2 AN: 2108

Alfa AF: 0.000416 Hom.: 0

Bravo AF: 0.000249

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	8.0
DANN	Benign	0.71
PhyloP100		0.37
Mutation Taster		=87/13	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: rs201886024; hg19: chr2-50699590;