chr1-233666969-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002245.4(KCNK1):​c.730C>T​(p.Leu244Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,611,994 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

KCNK1
NM_002245.4 missense

Scores

1
15
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.61
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KCNK1NM_002245.4 linkc.730C>T p.Leu244Phe missense_variant Exon 2 of 3 ENST00000366621.8 NP_002236.1 O00180A0A024R3T2
KCNK1XM_011544184.3 linkc.526C>T p.Leu176Phe missense_variant Exon 4 of 5 XP_011542486.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KCNK1ENST00000366621.8 linkc.730C>T p.Leu244Phe missense_variant Exon 2 of 3 1 NM_002245.4 ENSP00000355580.3 O00180

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152196
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000941
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000121
AC:
3
AN:
248266
Hom.:
0
AF XY:
0.00000745
AC XY:
1
AN XY:
134214
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:
0.0000465
Gnomad NFE exome
AF:
0.0000179
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000206
AC:
3
AN:
1459798
Hom.:
0
Cov.:
31
AF XY:
0.00000275
AC XY:
2
AN XY:
726240
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:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152196
Hom.:
0
Cov.:
32
AF XY:
0.0000403
AC XY:
3
AN XY:
74350
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000941
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Dec 18, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.730C>T (p.L244F) alteration is located in exon 2 (coding exon 2) of the KCNK1 gene. This alteration results from a C to T substitution at nucleotide position 730, causing the leucine (L) at amino acid position 244 to be replaced by a phenylalanine (F). 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
Benign
0.15
BayesDel_addAF
Pathogenic
0.21
D
BayesDel_noAF
Uncertain
0.080
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.74
D;D
Eigen
Uncertain
0.26
Eigen_PC
Uncertain
0.26
FATHMM_MKL
Uncertain
0.83
D
LIST_S2
Uncertain
0.86
D;D
M_CAP
Uncertain
0.11
D
MetaRNN
Uncertain
0.63
D;D
MetaSVM
Uncertain
0.67
D
MutationAssessor
Benign
1.6
L;.
PrimateAI
Uncertain
0.79
T
PROVEAN
Uncertain
-3.3
D;D
REVEL
Uncertain
0.61
Sift
Uncertain
0.0030
D;D
Sift4G
Uncertain
0.013
D;D
Polyphen
0.94
P;.
Vest4
0.50
MutPred
0.50
Loss of helix (P = 0.0626);.;
MVP
0.79
MPC
1.2
ClinPred
0.89
D
GERP RS
2.8
Varity_R
0.37
gMVP
0.76

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.15
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.

Other links and lift over

dbSNP: rs776795446; hg19: chr1-233802715; COSMIC: COSV100785688; COSMIC: COSV100785688; API