rs757453009

Positions:

• chr2-51027857-C-G
• chr2-51027857-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001330078.2(NRXN1):​c.417G>C​(p.Glu139Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,824 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NRXN1 NM_001330078.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.898

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NRXN1	NM_001330078.2	c.417G>C	p.Glu139Asp	missense_variant	2/23	ENST00000401669.7	NP_001317007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NRXN1	ENST00000401669.7	c.417G>C	p.Glu139Asp	missense_variant	2/23	5	NM_001330078.2	ENSP00000385017	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460824 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726782

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	.;T;.;.;T;.;T;T;T;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.045	D
MetaRNN	Uncertain	0.63	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Uncertain	2.7	M;M;M;.;.;.;.;.;.;.
MutationTaster	Benign	0.96	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.8	.;N;N;N;N;.;.;D;.;.
REVEL	Uncertain	0.58
Sift	Benign	0.092	.;T;T;T;T;.;.;D;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;.;D
Polyphen		0.65, 0.52	.;P;P;.;.;.;.;.;.;.
Vest4		0.56
MutPred		0.42		Loss of methylation at K141 (P = 0.0853);Loss of methylation at K141 (P = 0.0853);Loss of methylation at K141 (P = 0.0853);Loss of methylation at K141 (P = 0.0853);Loss of methylation at K141 (P = 0.0853);Loss of methylation at K141 (P = 0.0853);Loss of methylation at K141 (P = 0.0853);Loss of methylation at K141 (P = 0.0853);Loss of methylation at K141 (P = 0.0853);Loss of methylation at K141 (P = 0.0853);
MVP		0.85
MPC		0.97
ClinPred		0.89	D
GERP RS		5.0
Varity_R		0.23
gMVP		0.75

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

Publications

LitVar

Other links and lift over

dbSNP: rs757453009; hg19: chr2-51254995;