chr1-233666717-G-C

Variant names:

• chr1-233666717-G-C
• rs372727640
• NM_002245.4:c.478G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002245.4(KCNK1):​c.478G>C​(p.Val160Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V160F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KCNK1 NM_002245.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.95
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28321677).

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.478G>C	p.Val160Leu	missense	Exon 2 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.478G>C	p.Val160Leu	missense	Exon 2 of 3	ENSP00000355580.3	O00180
	KCNK1	ENST00000446915.1	TSL:3	c.232G>C	p.Val78Leu	missense	Exon 2 of 3	ENSP00000409626.1	Q5T5E6
	KCNK1	ENST00000918244.1		c.388+90G>C		intron	N/A	ENSP00000588303.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461888 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	19
DANN	Benign	0.89
DEOGEN2	Benign	0.26	T
Eigen	Benign	0.023
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.28	T
MetaSVM	Uncertain	0.38	D
MutationAssessor	Benign	1.9	M
PhyloP100		5.9
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.49	N
REVEL	Uncertain	0.32
Sift	Benign	0.60	T
Sift4G	Benign	0.63	T
Polyphen		0.68	P
Vest4		0.42
MutPred		0.40		Loss of helix (P = 0.079)
MVP		0.75
MPC		0.38
ClinPred		0.37	T
GERP RS		4.0
Varity_R		0.069
gMVP		0.81
Mutation Taster		=74/26	polymorphism

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: rs372727640; hg19: chr1-233802463;