16-67908770-G-C

Position:

• chr16-67908770-G-C

Variant summary

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

The NM_006742.3(PSKH1):​c.21G>C​(p.Lys7Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000208 in 1,441,066 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: 0.0000021 (0 hom.)
• Consequence: PSKH1 NM_006742.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.56

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.21G>C	p.Lys7Asn	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.21G>C	p.Lys7Asn	missense_variant	2/3	1	NM_006742.3	ENSP00000291041.4
PSKH1	ENST00000570631.5	c.21G>C	p.Lys7Asn	missense_variant	2/2	1		ENSP00000482880.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000208 AC: 3 AN: 1441066 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 AN XY: 713848

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: 0.00000182

Gnomad4 OTH exome AF: 0.0000168

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 21, 2023

The c.21G>C (p.K7N) alteration is located in exon 2 (coding exon 1) of the PSKH1 gene. This alteration results from a G to C substitution at nucleotide position 21, causing the lysine (K) at amino acid position 7 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	Pathogenic	0.88
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	.;T
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.64	D;D
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Uncertain	2.3	.;M
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.7	.;N
REVEL	Uncertain	0.30
Sift	Pathogenic	0.0	.;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.68
MutPred		0.28		Loss of methylation at K7 (P = 0.0012);Loss of methylation at K7 (P = 0.0012);
MVP		0.82
MPC		1.8
ClinPred		0.90	D
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.48
gMVP		0.53

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: rs1250866121; hg19: chr16-67942673;