14-88227500-T-C

Position:

• chr14-88227500-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_138317.3(KCNK10):​c.556A>G​(p.Lys186Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,450 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KCNK10 NM_138317.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.17

Genes affected

KCNK10 (HGNC:6273): (potassium two pore domain channel subfamily K member 10) The protein encoded by this gene belongs to the family of potassium channel proteins containing two pore-forming P domains. This channel is an open rectifier which primarily passes outward current under physiological K+ concentrations, and is stimulated strongly by arachidonic acid and to a lesser degree by membrane stretching, intracellular acidification, and general anaesthetics. Several alternatively spliced transcript variants encoding different isoforms have been identified for this gene. [provided by RefSeq, Sep 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.859

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNK10	NM_138317.3	c.556A>G	p.Lys186Glu	missense_variant	4/7	ENST00000319231.10	NP_612190.1
KCNK10	NM_138318.3	c.556A>G	p.Lys186Glu	missense_variant	4/7		NP_612191.1
KCNK10	NM_021161.5	c.541A>G	p.Lys181Glu	missense_variant	4/7		NP_066984.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNK10	ENST00000319231.10	c.556A>G	p.Lys186Glu	missense_variant	4/7	1	NM_138317.3	ENSP00000312811.5
KCNK10	ENST00000312350.9	c.556A>G	p.Lys186Glu	missense_variant	4/7	1		ENSP00000310568.5
KCNK10	ENST00000340700.9	c.541A>G	p.Lys181Glu	missense_variant	4/7	1		ENSP00000343104.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460450 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726478

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Sep 13, 2023

The c.556A>G (p.K186E) alteration is located in exon 4 (coding exon 4) of the KCNK10 gene. This alteration results from a A to G substitution at nucleotide position 556, causing the lysine (K) at amino acid position 186 to be replaced by a glutamic acid (E). 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	0.96
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.51	D;.;.
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.97	D;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Pathogenic	3.3	M;.;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.5	N;N;N
REVEL	Uncertain	0.43
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.95
MutPred		0.61		Gain of catalytic residue at K181 (P = 8e-04);.;.;
MVP		0.90
MPC		1.5
ClinPred		0.97	D
GERP RS		6.2
Varity_R		0.91
gMVP		0.97

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: rs1360713147; hg19: chr14-88693844;