2-51027954-G-T

Position:

• chr2-51027954-G-T

Variant summary

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

The NM_001330078.2(NRXN1):​c.320C>A​(p.Thr107Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,450,738 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T107M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: NRXN1 NM_001330078.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.52

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=0.21129322).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NRXN1	NM_001330078.2	c.320C>A	p.Thr107Lys	missense_variant	2/23	ENST00000401669.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NRXN1	ENST00000401669.7	c.320C>A	p.Thr107Lys	missense_variant	2/23	5	NM_001330078.2	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000428 AC: 1 AN: 233668 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 128784

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000931

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1450738 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 722190

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000831 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Pitt-Hopkins-like syndrome 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 13, 2022

This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 107 of the NRXN1 protein (p.Thr107Lys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with NRXN1-related conditions. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	24
DANN	Benign	0.89
DEOGEN2	Benign	0.18	.;T;.;.;T;.;T;T;T;.
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.017
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.78	T;T;D;T;T;T;D;D;D;D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.21	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.4	L;L;L;.;.;.;.;.;.;.
MutationTaster	Benign	0.99	N;N;N;N;N;N;N
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.58	.;N;N;N;N;.;.;N;.;.
REVEL	Uncertain	0.40
Sift	Benign	1.0	.;T;T;T;T;.;.;T;.;.
Sift4G	Benign	1.0	T;T;T;T;T;T;T;D;.;D
Polyphen		0.27, 0.0020	.;B;B;.;.;.;.;.;.;.
Vest4		0.36
MutPred		0.57		Gain of ubiquitination at T107 (P = 0.0185);Gain of ubiquitination at T107 (P = 0.0185);Gain of ubiquitination at T107 (P = 0.0185);Gain of ubiquitination at T107 (P = 0.0185);Gain of ubiquitination at T107 (P = 0.0185);Gain of ubiquitination at T107 (P = 0.0185);Gain of ubiquitination at T107 (P = 0.0185);Gain of ubiquitination at T107 (P = 0.0185);Gain of ubiquitination at T107 (P = 0.0185);Gain of ubiquitination at T107 (P = 0.0185);
MVP		0.67
MPC		0.79
ClinPred		0.12	T
GERP RS		5.0
Varity_R		0.052
gMVP		0.85

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: rs368549770; hg19: chr2-51255092;