chr2-51028169-G-T

Variant names:

• chr2-51028169-G-T
• rs55640811
• NM_001330078.2:c.105C>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS1

The NM_001330078.2(NRXN1):​c.105C>A​(p.Gly35Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00111 in 1,517,072 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G35G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00056 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (1 hom.)
• Consequence: NRXN1 NM_001330078.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:4
• Conservation: PhyloP100: -0.174
• 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: 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 2-51028169-G-T is Benign according to our data. Variant chr2-51028169-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 93584.
• BP7: Synonymous conserved (PhyloP=-0.174 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000558 (85/152276) while in subpopulation NFE AF = 0.000882 (60/68026). AF 95% confidence interval is 0.000703. There are 0 homozygotes in GnomAd4. There are 33 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.105C>A	p.Gly35Gly	synonymous	Exon 2 of 23	NP_001317007.1	Q9ULB1-5
	NRXN1	NM_001135659.3		c.105C>A	p.Gly35Gly	synonymous	Exon 2 of 24	NP_001129131.1	Q9ULB1-3
	NRXN1	NM_001330093.2		c.105C>A	p.Gly35Gly	synonymous	Exon 2 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.105C>A	p.Gly35Gly	synonymous	Exon 2 of 23	ENSP00000385017.2	Q9ULB1-5
	NRXN1	ENST00000404971.5	TSL:1	c.105C>A	p.Gly35Gly	synonymous	Exon 2 of 24	ENSP00000385142.1	Q9ULB1-3
	NRXN1	ENST00000625672.2	TSL:1	c.105C>A	p.Gly35Gly	synonymous	Exon 1 of 21	ENSP00000485887.1	Q9ULB1-2

Frequencies

GnomAD3 genomes AF: 0.000559 AC: 85 AN: 152158 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000882

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000500 AC: 66 AN: 131990 AF XY: 0.000405

Gnomad AFR exome AF: 0.000569

Gnomad AMR exome AF: 0.000423

Gnomad ASJ exome AF: 0.000220

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000154

Gnomad NFE exome AF: 0.000858

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00117 AC: 1598 AN: 1364796 Hom.: 1 Cov.: 31 AF XY: 0.00117 AC XY: 783 AN XY: 670370

African (AFR) AF: 0.000354 AC: 11 AN: 31106

American (AMR) AF: 0.000708 AC: 25 AN: 35288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21966

East Asian (EAS) AF: 0.00 AC: 0 AN: 37012

South Asian (SAS) AF: 0.00 AC: 0 AN: 73770

European-Finnish (FIN) AF: 0.000141 AC: 5 AN: 35506

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5472

European-Non Finnish (NFE) AF: 0.00140 AC: 1498 AN: 1068098

Other (OTH) AF: 0.00104 AC: 59 AN: 56578

GnomAD4 genome AF: 0.000558 AC: 85 AN: 152276 Hom.: 0 Cov.: 33 AF XY: 0.000443 AC XY: 33 AN XY: 74462

African (AFR) AF: 0.000313 AC: 13 AN: 41556

American (AMR) AF: 0.000653 AC: 10 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5140

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10624

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

European-Non Finnish (NFE) AF: 0.000882 AC: 60 AN: 68026

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

Alfa AF: 0.000727 Hom.: 0

Bravo AF: 0.000620

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	6.9
DANN	Benign	0.87
PhyloP100		-0.17
PromoterAI		0.091	Neutral
Mutation Taster		=99/1	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: rs55640811; hg19: chr2-51255307;