2-138670966-C-G

Position:

• chr2-138670966-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_007226.3(NXPH2):​c.751G>C​(p.Asp251His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NXPH2 NM_007226.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

Genes affected

NXPH2 (HGNC:8076): (neurexophilin 2) Predicted to enable signaling receptor binding activity. Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NXPH2	NM_007226.3	c.751G>C	p.Asp251His	missense_variant	2/2	ENST00000272641.4	NP_009157.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NXPH2	ENST00000272641.4	c.751G>C	p.Asp251His	missense_variant	2/2	1	NM_007226.3	ENSP00000272641.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Jun 11, 2024

The c.751G>C (p.D251H) alteration is located in exon 2 (coding exon 2) of the NXPH2 gene. This alteration results from a G to C substitution at nucleotide position 751, causing the aspartic acid (D) at amino acid position 251 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	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.47	T
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.051	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Uncertain	2.5	M
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-6.8	D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.89		Loss of phosphorylation at Y254 (P = 0.0783);
MVP		0.42
MPC		1.7
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.82
gMVP		0.88

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: rs1680404206; hg19: chr2-139428536;