X-153672651-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001366977.1(PNCK):c.115C>T(p.His39Tyr) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: PNCK NM_001366977.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.15

Genes affected

PNCK (HGNC:13415): (pregnancy up-regulated nonubiquitous CaM kinase) PNCK is a member of the calcium/calmodulin-dependent protein kinase family of protein serine/threonine kinases (see CAMK1; MIM 604998) (Gardner et al., 2000 [PubMed 10673339]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4001256).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PNCK	NM_001366977.1	c.115C>T	p.His39Tyr	missense_variant	3/12	ENST00000340888.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PNCK	ENST00000340888.8	c.115C>T	p.His39Tyr	missense_variant	3/12	5	NM_001366977.1	P1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD3 exomes AF: 0.0000171 AC: 3 AN: 175600 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 64044

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000220

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1091553 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 360479

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

ExAC AF: 0.00000824 AC: 1

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

Oct 10, 2023

The c.364C>T (p.H122Y) alteration is located in exon 3 (coding exon 3) of the PNCK gene. This alteration results from a C to T substitution at nucleotide position 364, causing the histidine (H) at amino acid position 122 to be replaced by a tyrosine (Y). 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	-0.37	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	21
Dann	Uncertain	0.98
DEOGEN2	Benign	0.055	T;T;.;.;.;T;.;T;T;.;T;T;T
FATHMM_MKL	Uncertain	0.77	D
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.40	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	0.44	N;N;N;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	0.98	N;N;N;N;N;N
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.9	N;N;N;N;N;N;N;D;D;N;N;D;D
REVEL	Benign	0.13
Sift	Uncertain	0.0030	D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0060	D;D;D;D;D;D;.;.;.;.;.;.;.
Polyphen		0.81	P;P;.;.;P;.;.;.;.;.;.;.;.
Vest4		0.27
MutPred		0.47		Gain of phosphorylation at H39 (P = 0.0728);Gain of phosphorylation at H39 (P = 0.0728);Gain of phosphorylation at H39 (P = 0.0728);.;.;Gain of phosphorylation at H39 (P = 0.0728);Gain of phosphorylation at H39 (P = 0.0728);Gain of phosphorylation at H39 (P = 0.0728);Gain of phosphorylation at H39 (P = 0.0728);Gain of phosphorylation at H39 (P = 0.0728);Gain of phosphorylation at H39 (P = 0.0728);Gain of phosphorylation at H39 (P = 0.0728);Gain of phosphorylation at H39 (P = 0.0728);
MVP		0.80
MPC		1.3
ClinPred		0.62	D
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.30
gMVP		0.86

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

LitVar

Other links and lift over

dbSNP: rs782773576; hg19: chrX-152938106;