11-64607734-G-C

Position:

• chr11-64607734-G-C

Variant summary

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

The NM_015080.4(NRXN2):​c.4601C>G​(p.Pro1534Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,420,046 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NRXN2 NM_015080.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 2.59

Genes affected

NRXN2 (HGNC:8009): (neurexin 2) This gene encodes a member of the neurexin gene family. The products of these genes function as cell adhesion molecules and receptors in the vertebrate nervous system. These genes utilize two promoters. The majority of transcripts are produced from the upstream promoter and encode alpha-neurexin isoforms while a smaller number of transcripts are produced from the downstream promoter and encode beta-neuresin isoforms. The alpha-neurexins contain epidermal growth factor-like (EGF-like) sequences and laminin G domains, and have been shown to interact with neurexophilins. The beta-neurexins lack EGF-like sequences and contain fewer laminin G domains than alpha-neurexins. Alternative splicing and the use of alternative promoters may generate thousands of transcript variants (PMID: 12036300, PMID: 11944992).[provided by RefSeq, Jun 2010]

NRXN2 (HGNC:):

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=0.18817845).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NRXN2	NM_015080.4	c.4601C>G	p.Pro1534Arg	missense_variant	23/23	ENST00000265459.11	NP_055895.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NRXN2	ENST00000265459.11	c.4601C>G	p.Pro1534Arg	missense_variant	23/23	5	NM_015080.4	ENSP00000265459.5
NRXN2	ENST00000704782.1	c.4610C>G	p.Pro1537Arg	missense_variant	22/22			ENSP00000516031.1
NRXN2	ENST00000704781.1	c.4262-234C>G		intron_variant				ENSP00000516029.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1420046 Hom.: 0 Cov.: 34 AF XY: 0.00000285 AC XY: 2 AN XY: 702360

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: 0.0000248

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

NRXN2-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 30, 2024

The NRXN2 c.4601C>G variant is predicted to result in the amino acid substitution p.Pro1534Arg. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.088	T;T;.;T;.
Eigen	Benign	0.026
Eigen_PC	Benign	0.079
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.90	D;.;T;T;T
M_CAP	Benign	0.082	D
MetaRNN	Benign	0.19	T;T;T;T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.5	.;L;.;L;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.4	N;N;N;N;N
REVEL	Benign	0.085
Sift	Uncertain	0.013	D;T;T;T;T
Sift4G	Uncertain	0.0020	D;D;D;D;D
Polyphen		1.0	D;P;B;P;.
Vest4		0.24
MutPred		0.26		.;Gain of MoRF binding (P = 0.0089);.;Gain of MoRF binding (P = 0.0089);.;
MVP		0.15
MPC		1.1
ClinPred		0.40	T
GERP RS		3.4
Varity_R		0.11
gMVP		0.32

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-64375206;