chr1-215194989-C-T

Variant names:

• chr1-215194989-C-T
• rs752327424
• NM_001017425.3:c.860C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001017425.3(KCNK2):​c.860C>T​(p.Pro287Leu) variant causes a missense change involving the alteration of a conserved nucleotide. 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: 32)
• Consequence: KCNK2 NM_001017425.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.84
• Publications: 0 publications found

Genes affected

KCNK2 (HGNC:6277): (potassium two pore domain channel subfamily K member 2) This gene encodes one of the members of the two-pore-domain background potassium channel protein family. This type of potassium channel is formed by two homodimers that create a channel that leaks potassium out of the cell to control resting membrane potential. The channel can be opened, however, by certain anesthetics, membrane stretching, intracellular acidosis, and heat. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.807

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001017425.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNK2	NM_001017425.3	MANE Select	c.860C>T	p.Pro287Leu	missense	Exon 6 of 7	NP_001017425.2	O95069-1
	KCNK2	NM_001017424.3		c.848C>T	p.Pro283Leu	missense	Exon 6 of 7	NP_001017424.1	U3N834
	KCNK2	NM_014217.4		c.815C>T	p.Pro272Leu	missense	Exon 6 of 7	NP_055032.1	O95069-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNK2	ENST00000444842.7	TSL:1 MANE Select	c.860C>T	p.Pro287Leu	missense	Exon 6 of 7	ENSP00000394033.2	O95069-1
	KCNK2	ENST00000391895.6	TSL:1	c.848C>T	p.Pro283Leu	missense	Exon 6 of 7	ENSP00000375765.2	O95069-3
	KCNK2	ENST00000391894.6	TSL:1	c.815C>T	p.Pro272Leu	missense	Exon 6 of 7	ENSP00000375764.2	O95069-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.037	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L
PhyloP100		7.8
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.5	D
REVEL	Uncertain	0.44
Sift	Benign	0.11	T
Sift4G	Benign	0.10	T
Polyphen		1.0	D
Vest4		0.82
MutPred		0.59		Gain of helix (P = 0.0854)
MVP		0.57
MPC		1.7
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.37
gMVP		0.97
Mutation Taster		=34/66	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs752327424; hg19: chr1-215368332;