2-138671169-T-C

Variant names:

• chr2-138671169-T-C
• rs772378574
• NM_007226.3:c.548A>G

Variant summary

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

The NM_007226.3(NXPH2):​c.548A>G​(p.Lys183Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,461,688 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: NXPH2 NM_007226.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NXPH2	NM_007226.3	c.548A>G	p.Lys183Arg	missense_variant	Exon 2 of 2	ENST00000272641.4	NP_009157.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NXPH2	ENST00000272641.4	c.548A>G	p.Lys183Arg	missense_variant	Exon 2 of 2	1	NM_007226.3	ENSP00000272641.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000241 AC: 6 AN: 249030 Hom.: 0 AF XY: 0.0000296 AC XY: 4 AN XY: 135116

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: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1461688 Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12 AN XY: 727126

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000166 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 30, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.548A>G (p.K183R) alteration is located in exon 2 (coding exon 2) of the NXPH2 gene. This alteration results from a A to G substitution at nucleotide position 548, causing the lysine (K) at amino acid position 183 to be replaced by an arginine (R). 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	0.13
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.088	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.51	D
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	2.0	M
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.15
Sift	Benign	0.31	T
Sift4G	Benign	0.20	T
Polyphen		0.87	P
Vest4		0.70
MutPred		0.55		Loss of ubiquitination at K183 (P = 0.0034);
MVP		0.36
MPC		1.4
ClinPred		0.58	D
GERP RS		5.7
Varity_R		0.25
gMVP		0.51

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: rs772378574; hg19: chr2-139428739;