2-51027952-G-C

Position:

• chr2-51027952-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001330078.2(NRXN1):​c.322C>G​(p.Pro108Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,450,984 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NRXN1 NM_001330078.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.04

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19376343).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NRXN1	NM_001330078.2	c.322C>G	p.Pro108Ala	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.322C>G	p.Pro108Ala	missense_variant	2/23	5	NM_001330078.2	ENSP00000385017.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000855 AC: 2 AN: 234050 Hom.: 0 AF XY: 0.00000776 AC XY: 1 AN XY: 128938

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000329

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000930

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1450984 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 722310

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: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000832 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 07, 2017

A variant of uncertain significance has been identified in the NRXN1 gene. The P108A variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The P108A variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P108A variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals; however, Alanine is observed at this position in evolution. In silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	20
DANN	Benign	0.85
DEOGEN2	Benign	0.20	.;T;.;.;T;.;T;T;T;.
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.88	D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.19	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.15	N;N;N;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.79	.;N;N;N;N;.;.;N;.;.
REVEL	Benign	0.21
Sift	Benign	0.73	.;T;T;T;T;.;.;T;.;.
Sift4G	Benign	0.21	T;T;T;T;T;T;T;T;.;T
Polyphen		0.0040, 0.0	.;B;B;.;.;.;.;.;.;.
Vest4		0.20
MutPred		0.55		Gain of MoRF binding (P = 0.0953);Gain of MoRF binding (P = 0.0953);Gain of MoRF binding (P = 0.0953);Gain of MoRF binding (P = 0.0953);Gain of MoRF binding (P = 0.0953);Gain of MoRF binding (P = 0.0953);Gain of MoRF binding (P = 0.0953);Gain of MoRF binding (P = 0.0953);Gain of MoRF binding (P = 0.0953);Gain of MoRF binding (P = 0.0953);
MVP		0.22
MPC		0.58
ClinPred		0.045	T
GERP RS		5.0
Varity_R		0.064
gMVP		0.42

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: rs199784029; hg19: chr2-51255090;