8-86048737-C-T

Variant names:

• chr8-86048737-C-T
• rs748048916
• NM_033126.3:c.883G>A

Variant summary

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

The NM_033126.3(PSKH2):​c.883G>A​(p.Asp295Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,458,352 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: 0.0000014 (0 hom.)
• Consequence: PSKH2 NM_033126.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.62

Genes affected

PSKH2 (HGNC:18997): (protein serine kinase H2) Predicted to enable ATP binding activity; protein serine kinase activity; and protein serine/threonine kinase activity. Predicted to be involved in protein phosphorylation. [provided by Alliance of Genome Resources, Apr 2022]

ATP6V0D2 (HGNC:18266): (ATPase H+ transporting V0 subunit d2) Predicted to enable proton transmembrane transporter activity. Predicted to be involved in vacuolar acidification and vacuolar transport. Located in apical plasma membrane. Part of vacuolar proton-transporting V-type ATPase complex. [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
PSKH2	NM_033126.3	c.883G>A	p.Asp295Asn	missense_variant	Exon 3 of 3	ENST00000276616.3	NP_149117.1
PSKH2	XM_017013929.2	c.1240G>A	p.Asp414Asn	missense_variant	Exon 5 of 5		XP_016869418.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSKH2	ENST00000276616.3	c.883G>A	p.Asp295Asn	missense_variant	Exon 3 of 3	1	NM_033126.3	ENSP00000276616.2
ATP6V0D2	ENST00000521564.1	c.-262-17651C>T		intron_variant	Intron 1 of 3	3		ENSP00000429731.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458352 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 724978

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: 9.01e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000378

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 14, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.883G>A (p.D295N) alteration is located in exon 3 (coding exon 3) of the PSKH2 gene. This alteration results from a G to A substitution at nucleotide position 883, causing the aspartic acid (D) at amino acid position 295 to be replaced by an asparagine (N). 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	0.15
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.026	T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.025	T
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.92	L
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.23
Sift	Benign	0.070	T
Sift4G	Benign	0.068	T
Polyphen		1.0	D
Vest4		0.28
MutPred		0.69		Gain of methylation at K294 (P = 0.0734);
MVP		0.71
MPC		0.16
ClinPred		0.92	D
GERP RS		3.0
Varity_R		0.17
gMVP		0.45

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: rs748048916; hg19: chr8-87060966;