X-153670772-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001366977.1(PNCK):c.866G>A(p.Arg289Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000736 in 1,209,479 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 24 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R289W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., 10 hem., cov: 25)
  • Exomes 𝑓: 0.000040 (0 hom. 14 hem.)
• Consequence: PNCK NM_001366977.1 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.55

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01944992).
• BP6: Variant X-153670772-C-T is Benign according to our data. Variant chrX-153670772-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2341793.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAd at 10 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PNCK	NM_001366977.1	c.866G>A	p.Arg289Gln	missense_variant	10/12	ENST00000340888.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PNCK	ENST00000340888.8	c.866G>A	p.Arg289Gln	missense_variant	10/12	5	NM_001366977.1	P1

Frequencies

GnomAD3 genomes AF: 0.000400 AC: 45 AN: 112459 Hom.: 0 Cov.: 25 AF XY: 0.000289 AC XY: 10 AN XY: 34619

Gnomad AFR AF: 0.00139

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000926

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000110 AC: 20 AN: 182321 Hom.: 0 AF XY: 0.0000598 AC XY: 4 AN XY: 66863

Gnomad AFR exome AF: 0.00114

Gnomad AMR exome AF: 0.0000366

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.000666

GnomAD4 exome AF: 0.0000401 AC: 44 AN: 1097020 Hom.: 0 Cov.: 32 AF XY: 0.0000386 AC XY: 14 AN XY: 362508

Gnomad4 AFR exome AF: 0.00106

Gnomad4 AMR exome AF: 0.0000853

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.0000370

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000238

Gnomad4 OTH exome AF: 0.000152

GnomAD4 genome AF: 0.000400 AC: 45 AN: 112459 Hom.: 0 Cov.: 25 AF XY: 0.000289 AC XY: 10 AN XY: 34619

Gnomad4 AFR AF: 0.00139

Gnomad4 AMR AF: 0.0000926

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000188

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000689 Hom.: 1

Bravo AF: 0.000567

ESP6500AA AF: 0.00130 AC: 5

ESP6500EA AF: 0.000446 AC: 3

ExAC AF: 0.000124 AC: 15

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 12, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	14
Dann	Benign	0.86
DEOGEN2	Benign	0.028	T;T;.;.;.
FATHMM_MKL	Benign	0.066	N
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.019	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.3	N;N;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.31	N;N;N;N;N
REVEL	Benign	0.071
Sift	Benign	0.90	T;T;T;T;T
Sift4G	Benign	0.38	T;T;T;T;T
Polyphen		0.0	B;B;.;.;B
Vest4		0.20
MVP		0.78
MPC		0.63
ClinPred		0.0047	T
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.042
gMVP		0.12

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: rs146644423; hg19: chrX-152936227; COSMIC: COSV61744010; COSMIC: COSV61744010;