1-233614406-C-A

Variant names:

• chr1-233614406-C-A
• NM_002245.4:c.235C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002245.4(KCNK1):​c.235C>A​(p.Leu79Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,802 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KCNK1 NM_002245.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.72
• Publications: 0 publications found

Genes affected

KCNK1 (HGNC:6272): (potassium two pore domain channel subfamily K member 1) This gene encodes one of the members of the superfamily of potassium channel proteins containing two pore-forming P domains. The product of this gene has not been shown to be a functional channel, however, it may require other non-pore-forming proteins for activity. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002245.4. 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
	KCNK1	NM_002245.4	MANE Select	c.235C>A	p.Leu79Met	missense	Exon 1 of 3	NP_002236.1	O00180

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNK1	ENST00000366621.8	TSL:1 MANE Select	c.235C>A	p.Leu79Met	missense	Exon 1 of 3	ENSP00000355580.3	O00180
	KCNK1	ENST00000918244.1		c.235C>A	p.Leu79Met	missense	Exon 1 of 3	ENSP00000588303.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459802 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 725990

African (AFR) AF: 0.00 AC: 0 AN: 33438

American (AMR) AF: 0.00 AC: 0 AN: 44530

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26052

East Asian (EAS) AF: 0.00 AC: 0 AN: 39634

South Asian (SAS) AF: 0.00 AC: 0 AN: 85712

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53108

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111282

Other (OTH) AF: 0.00 AC: 0 AN: 60284

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	0.59
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.075	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		1.7
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.17
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.49
MutPred		0.38		Gain of disorder (P = 0.16)
MVP		0.39
MPC		1.1
ClinPred		0.98	D
GERP RS		2.4
PromoterAI		-0.028	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.60
gMVP		0.64
Mutation Taster		=34/66	disease causing

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

Other links and lift over

hg19: chr1-233750152;