chr16-67909006-A-G

Position:

• chr16-67909006-A-G

Variant summary

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

The NM_006742.3(PSKH1):​c.257A>G​(p.Tyr86Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PSKH1 NM_006742.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.95

Genes affected

PSKH1 (HGNC:9529): (protein serine kinase H1) Predicted to enable protein kinase activity. Predicted to act upstream of or within determination of left/right symmetry; heart development; and protein phosphorylation. Located in cytosol and nuclear speck. [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/exons	MANE	Protein	UniProt
PSKH1	NM_006742.3	c.257A>G	p.Tyr86Cys	missense_variant	2/3	ENST00000291041.6	NP_006733.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PSKH1	ENST00000291041.6	c.257A>G	p.Tyr86Cys	missense_variant	2/3	1	NM_006742.3	ENSP00000291041.4
PSKH1	ENST00000570631.5	c.257A>G	p.Tyr86Cys	missense_variant	2/2	1		ENSP00000482880.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000151

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

Dec 01, 2023

The c.257A>G (p.Y86C) alteration is located in exon 2 (coding exon 1) of the PSKH1 gene. This alteration results from a A to G substitution at nucleotide position 257, causing the tyrosine (Y) at amino acid position 86 to be replaced by a cysteine (C). 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	0.99
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	.;T
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.038	D
MetaRNN	Uncertain	0.73	D;D
MetaSVM	Benign	-0.73	T
MutationAssessor	Uncertain	2.2	.;M
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-3.6	.;D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0020	.;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		1.0	.;D
Vest4		0.82
MutPred		0.34		Gain of methylation at K85 (P = 0.0279);Gain of methylation at K85 (P = 0.0279);
MVP		0.88
MPC		1.9
ClinPred		0.98	D
GERP RS		4.8
Varity_R		0.51
gMVP		0.63

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: rs936187440; hg19: chr16-67942909;