14-88185728-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_138317.3(KCNK10):c.1439C>T(p.Thr480Ile) 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNK10 NM_138317.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.03

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20640549).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNK10	NM_138317.3	c.1439C>T	p.Thr480Ile	missense_variant	7/7	ENST00000319231.10
KCNK10	NM_138318.3	c.1439C>T	p.Thr480Ile	missense_variant	7/7
KCNK10	NM_021161.5	c.1424C>T	p.Thr475Ile	missense_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNK10	ENST00000319231.10	c.1439C>T	p.Thr480Ile	missense_variant	7/7	1	NM_138317.3	P1
KCNK10	ENST00000312350.9	c.1439C>T	p.Thr480Ile	missense_variant	7/7	1
KCNK10	ENST00000340700.9	c.1424C>T	p.Thr475Ile	missense_variant	7/7	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 39

GnomAD4 genome Cov.: 32

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

May 01, 2022

The c.1439C>T (p.T480I) alteration is located in exon 7 (coding exon 7) of the KCNK10 gene. This alteration results from a C to T substitution at nucleotide position 1439, causing the threonine (T) at amino acid position 480 to be replaced by an isoleucine (I). 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	0.20
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.18
Cadd	Benign	20
Dann	Uncertain	1.0
DEOGEN2	Benign	0.0084	T;.;.
Eigen	Benign	-0.15
Eigen_PC	Benign	0.050
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Benign	0.069	D
MetaRNN	Benign	0.21	T;T;T
MetaSVM	Uncertain	-0.058	T
MutationAssessor	Benign	0.81	L;.;.
MutationTaster	Benign	0.81	D;D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.67	N;N;N
REVEL	Benign	0.27
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.017	D;D;D
Polyphen		0.037	B;.;.
Vest4		0.29
MutPred		0.27		Gain of catalytic residue at R477 (P = 0.0146);.;.;
MVP		0.92
MPC		0.62
ClinPred		0.46	T
GERP RS		4.8
Varity_R		0.086
gMVP		0.46

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-88652072;