2-50506533-C-T

Variant names:

• chr2-50506533-C-T
• rs80293130
• NM_001330078.2:c.2459G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001330078.2(NRXN1):​c.2459G>A​(p.Ser820Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000255 in 1,613,096 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S820G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (2 hom.)
• Consequence: NRXN1 NM_001330078.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:2
• Conservation: PhyloP100: 3.31
• Publications: 5 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.051980168).
• BP6: Variant 2-50506533-C-T is Benign according to our data. Variant chr2-50506533-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 206242.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000151 (23/152176) while in subpopulation SAS AF = 0.00104 (5/4818). AF 95% confidence interval is 0.000409. There are 0 homozygotes in GnomAd4. There are 12 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRXN1	NM_001330078.2	MANE Select	c.2459G>A	p.Ser820Asn	missense	Exon 13 of 23	NP_001317007.1
	NRXN1	NM_001135659.3		c.2579G>A	p.Ser860Asn	missense	Exon 14 of 24	NP_001129131.1
	NRXN1	NM_001330093.2		c.2456G>A	p.Ser819Asn	missense	Exon 13 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.2459G>A	p.Ser820Asn	missense	Exon 13 of 23	ENSP00000385017.2
	NRXN1	ENST00000404971.5	TSL:1	c.2579G>A	p.Ser860Asn	missense	Exon 14 of 24	ENSP00000385142.1
	NRXN1	ENST00000625672.2	TSL:1	c.2435G>A	p.Ser812Asn	missense	Exon 11 of 21	ENSP00000485887.1

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152058 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000258 AC: 64 AN: 248062 AF XY: 0.000327

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000249

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000266 AC: 388 AN: 1460920 Hom.: 2 Cov.: 31 AF XY: 0.000316 AC XY: 230 AN XY: 726702

African (AFR) AF: 0.0000299 AC: 1 AN: 33450

American (AMR) AF: 0.0000224 AC: 1 AN: 44624

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.00110 AC: 95 AN: 86184

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53356

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 0.000251 AC: 279 AN: 1111450

Other (OTH) AF: 0.000182 AC: 11 AN: 60334

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152176 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74398

African (AFR) AF: 0.0000482 AC: 2 AN: 41512

American (AMR) AF: 0.00 AC: 0 AN: 15280

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

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

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000305 Hom.: 0

Bravo AF: 0.000113

ESP6500AA AF: 0.000257 AC: 1

ESP6500EA AF: 0.000363 AC: 3

ExAC AF: 0.000215 AC: 26

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000238

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	not provided (3)
-	1	-	Inborn genetic diseases (1)
-	1	-	not specified (1)
-	-	1	Pitt-Hopkins-like syndrome 2 (1)
-	1	-	Pitt-Hopkins-like syndrome 2;C3808494:Chromosome 2p16.3 deletion syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.16
Eigen_PC	Benign	0.093
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.052	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	-0.23	N
PhyloP100		3.3
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.88	N
REVEL	Benign	0.27
Sift	Benign	0.37	T
Sift4G	Benign	0.49	T
Polyphen		0.0	B
Vest4		0.33
MVP		0.043
MPC		0.23
ClinPred		0.050	T
GERP RS		5.7
Varity_R		0.29
gMVP		0.42
Mutation Taster		=100/0	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: rs80293130; hg19: chr2-50733671;