Genetic Variant KCNK1:p.Phe78Leu (chr1-233614405-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002245.4(KCNK1):c.234C>G(p.Phe78Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000151 in 1,459,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

KCNK1
NM_002245.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.80

Variant links:

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]

KCNK1 links:

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ACMG classification

Classification made for transcript

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=0.1774337).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNK1	NM_002245.4 link	c.234C>G	p.Phe78Leu	missense_variant	Exon 1 of 3	ENST00000366621.8	NP_002236.1	O00180A0A024R3T2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNK1	ENST00000366621.8 link	c.234C>G	p.Phe78Leu	missense_variant	Exon 1 of 3	1	NM_002245.4	ENSP00000355580.3		O00180

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000409

AC:

AN:

244518

Hom.:

AF XY:

0.00000753

AC XY:

AN XY:

132840

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000908

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000151

AC:

AN:

1459778

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

726008

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000171

Gnomad4 OTH exome

AF:

0.0000498

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000468

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 28, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.234C>G (p.F78L) alteration is located in exon 1 (coding exon 1) of the KCNK1 gene. This alteration results from a C to G substitution at nucleotide position 234, causing the phenylalanine (F) at amino acid position 78 to be replaced by a leucine (L). 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

0.95

BayesDel_addAF

Benign

-0.023

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.32

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.33

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.74

M_CAP

Benign

0.066

MetaRNN

Benign

0.18

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-2.2

REVEL

Benign

0.19

Sift

Benign

0.32

Sift4G

Benign

0.89

Polyphen

0.012

Vest4

0.41

MutPred

0.49

Loss of helix (P = 0.0072);

MVP

0.70

MPC

0.44

ClinPred

0.32

GERP RS

3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.85

gMVP

0.83

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over