11-64607920-G-T

Variant summary

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

The NM_015080.4(NRXN2):c.4415C>A(p.Pro1472His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: NRXN2 NM_015080.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.45

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]

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=0.18597966).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NRXN2	NM_015080.4	c.4415C>A	p.Pro1472His	missense_variant	23/23	ENST00000265459.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NRXN2	ENST00000265459.11	c.4415C>A	p.Pro1472His	missense_variant	23/23	5	NM_015080.4	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 28, 2023

The c.4415C>A (p.P1472H) alteration is located in exon 23 (coding exon 22) of the NRXN2 gene. This alteration results from a C to A substitution at nucleotide position 4415, causing the proline (P) at amino acid position 1472 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
Cadd	Uncertain	25
Dann	Uncertain	0.98
DEOGEN2	Benign	0.077	T;T;.;T;.
Eigen	Benign	-0.095
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.84	T;.;T;T;T
M_CAP	Pathogenic	0.65	D
MetaRNN	Benign	0.19	T;T;T;T;T
MetaSVM	Benign	-0.86	T
MutationTaster	Benign	0.75	N;N;N;N;N
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.1	N;N;N;N;N
REVEL	Benign	0.070
Sift	Uncertain	0.011	D;D;D;D;D
Sift4G	Uncertain	0.0050	D;D;D;D;D
Polyphen		0.60	P;D;D;D;.
Vest4		0.15
MutPred		0.17		.;Loss of relative solvent accessibility (P = 0.0186);.;Loss of relative solvent accessibility (P = 0.0186);.;
MVP		0.043
MPC		1.4
ClinPred		0.36	T
GERP RS		2.8
Varity_R		0.13
gMVP		0.21

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: rs111625451; hg19: chr11-64375392;