chr6-39191720-G-A

Position:

• chr6-39191720-G-A

Variant summary

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

The NM_003740.4(KCNK5):​c.670C>T​(p.Arg224Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: KCNK5 NM_003740.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.31

Genes affected

KCNK5 (HGNC:6280): (potassium two pore domain channel subfamily K member 5) This gene encodes one of the members of the superfamily of potassium channel proteins containing two pore-forming P domains. The message for this gene is mainly expressed in the cortical distal tubules and collecting ducts of the kidney. The protein is highly sensitive to external pH and this, in combination with its expression pattern, suggests it may play an important role in renal potassium transport. [provided by RefSeq, Jul 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, 0.917

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNK5	NM_003740.4	c.670C>T	p.Arg224Cys	missense_variant	5/5	ENST00000359534.4
KCNK5	XM_005249456.2	c.661C>T	p.Arg221Cys	missense_variant	5/5
KCNK5	XM_006715235.2	c.124C>T	p.Arg42Cys	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNK5	ENST00000359534.4	c.670C>T	p.Arg224Cys	missense_variant	5/5	1	NM_003740.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

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

Jul 08, 2022

The c.670C>T (p.R224C) alteration is located in exon 5 (coding exon 5) of the KCNK5 gene. This alteration results from a C to T substitution at nucleotide position 670, causing the arginine (R) at amino acid position 224 to be replaced by a cysteine (C). 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	0.72
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Benign	-0.79	T
MutationAssessor	Pathogenic	3.0	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-6.1	D
REVEL	Uncertain	0.49
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.68	P
Vest4		0.85
MutPred		0.81		Loss of helix (P = 0.0558);
MVP		0.62
MPC		2.0
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.63
gMVP		0.95

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: chr6-39159496; COSMIC: COSV63988531;