8-86064447-T-G

Position:

• chr8-86064447-T-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_033126.3(PSKH2):​c.370A>C​(p.Met124Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.00049 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PSKH2 NM_033126.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.235

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]

PSKH2 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02969116).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSKH2	NM_033126.3	c.370A>C	p.Met124Leu	missense_variant	2/3	ENST00000276616.3	NP_149117.1
PSKH2	XM_017013929.2	c.727A>C	p.Met243Leu	missense_variant	4/5		XP_016869418.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PSKH2	ENST00000276616.3	c.370A>C	p.Met124Leu	missense_variant	2/3	1	NM_033126.3	ENSP00000276616.2
ATP6V0D2	ENST00000521564.1	c.-262-1941T>G		intron_variant		3		ENSP00000429731.1
PSKH2	ENST00000517981.5	n.353A>C		non_coding_transcript_exon_variant	3/3	3
PSKH2	ENST00000523010.1	n.413A>C		non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000486 AC: 706 AN: 1453998 Hom.: 0 Cov.: 34 AF XY: 0.000424 AC XY: 307 AN XY: 723614

Gnomad4 AFR exome AF: 0.000390

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000586

Gnomad4 OTH exome AF: 0.000433

GnomAD4 genome Cov.: 32

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

Aug 26, 2024

The c.370A>C (p.M124L) alteration is located in exon 2 (coding exon 2) of the PSKH2 gene. This alteration results from a A to C substitution at nucleotide position 370, causing the methionine (M) at amino acid position 124 to be replaced by a leucine (L). 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	0.095
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.043
DANN	Benign	0.54
DEOGEN2	Benign	0.00073	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.19	T
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.030	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.5	N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.25	N
REVEL	Benign	0.062
Sift	Benign	0.65	T
Sift4G	Benign	0.65	T
Polyphen		0.0	B
Vest4		0.17
MutPred		0.47		Loss of MoRF binding (P = 0.0832);
MVP		0.10
MPC		0.064
ClinPred		0.052	T
GERP RS		-8.9
Varity_R		0.053
gMVP		0.065

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr8-87076676;