X-153673078-T-C

Position:

• chrX-153673078-T-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001039582.3(PNCK):​c.248A>G​(p.Asp83Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000463 in 1,080,925 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. 11/19 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000046 (0 hom. 2 hem.)
• Consequence: PNCK NM_001039582.3 missense, splice_region
• Scores: Splicing: ADA: 0.00005998
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.51

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]

PNCK (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High Hemizygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PNCK	NM_001366977.1	c.-2A>G		splice_region_variant	2/12	ENST00000340888.8	NP_001353906.1
PNCK	NM_001366977.1	c.-2A>G		5_prime_UTR_variant	2/12	ENST00000340888.8	NP_001353906.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PNCK	ENST00000340888.8	c.-2A>G		splice_region_variant	2/12	5	NM_001366977.1	ENSP00000340586.4
PNCK	ENST00000340888.8	c.-2A>G		5_prime_UTR_variant	2/12	5	NM_001366977.1	ENSP00000340586.4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000463 AC: 5 AN: 1080925 Hom.: 0 Cov.: 33 AF XY: 0.00000571 AC XY: 2 AN XY: 349973

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: 0.00000602

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ExAC AF: 0.0000166 AC: 2

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

Nov 07, 2022

The c.248A>G (p.D83G) alteration is located in exon 2 (coding exon 2) of the PNCK gene. This alteration results from a A to G substitution at nucleotide position 248, causing the aspartic acid (D) at amino acid position 83 to be replaced by a glycine (G). 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
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	9.7
DANN	Uncertain	0.98
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.40	T;T
M_CAP	Pathogenic	0.89	D
MetaRNN	Uncertain	0.55	D;T
MetaSVM	Benign	-0.87	T
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.046
Sift	Uncertain	0.0090	D;D
Sift4G	Benign	0.15	T;T
Polyphen		0.97	.;D
Vest4		0.26
MutPred		0.37		.;Gain of MoRF binding (P = 0.0312);
MVP		0.70
MPC		1.0
ClinPred		0.40	T
GERP RS		1.1
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000060
dbscSNV1_RF	Benign	0.016
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: rs782569431; hg19: chrX-152938533;