6-39191441-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_003740.4(KCNK5):ā€‹c.949G>Cā€‹(p.Gly317Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,406 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000013 ( 0 hom., cov: 31)
Exomes š‘“: 0.0000021 ( 0 hom. )

Consequence

KCNK5
NM_003740.4 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.32
Variant links:
Genes affected
KCNK5 (HGNC:6280): (potassium two pore domain channel subfamily K member 5) This gene encodes one of the members of the superfamily of potassium channel proteins containing two pore-forming P domains. The message for this gene is mainly expressed in the cortical distal tubules and collecting ducts of the kidney. The protein is highly sensitive to external pH and this, in combination with its expression pattern, suggests it may play an important role in renal potassium transport. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.032008797).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
KCNK5NM_003740.4 linkuse as main transcriptc.949G>C p.Gly317Arg missense_variant 5/5 ENST00000359534.4
KCNK5XM_005249456.2 linkuse as main transcriptc.940G>C p.Gly314Arg missense_variant 5/5
KCNK5XM_006715235.2 linkuse as main transcriptc.403G>C p.Gly135Arg missense_variant 3/3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
KCNK5ENST00000359534.4 linkuse as main transcriptc.949G>C p.Gly317Arg missense_variant 5/51 NM_003740.4 P1

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
151990
Hom.:
0
Cov.:
31
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:
0.000195
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000199
AC:
5
AN:
250832
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135672
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000272
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461298
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
727000
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000756
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152108
Hom.:
0
Cov.:
31
AF XY:
0.0000269
AC XY:
2
AN XY:
74350
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000195
Gnomad4 SAS
AF:
0.000208
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
ExAC
AF:
0.0000247
AC:
3

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsDec 14, 2023The c.949G>C (p.G317R) alteration is located in exon 5 (coding exon 5) of the KCNK5 gene. This alteration results from a G to C substitution at nucleotide position 949, causing the glycine (G) at amino acid position 317 to be replaced by an arginine (R). 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
0.11
BayesDel_addAF
Benign
-0.43
T
BayesDel_noAF
Benign
-0.56
CADD
Benign
11
DANN
Benign
0.97
DEOGEN2
Benign
0.10
T
Eigen
Benign
-0.88
Eigen_PC
Benign
-0.80
FATHMM_MKL
Benign
0.29
N
LIST_S2
Benign
0.64
T
M_CAP
Benign
0.0039
T
MetaRNN
Benign
0.032
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.5
L
MutationTaster
Benign
1.0
N
PrimateAI
Uncertain
0.54
T
PROVEAN
Benign
-1.1
N
REVEL
Benign
0.048
Sift
Benign
0.094
T
Sift4G
Benign
0.64
T
Polyphen
0.0
B
Vest4
0.28
MutPred
0.27
Gain of MoRF binding (P = 0.013);
MVP
0.25
MPC
0.80
ClinPred
0.098
T
GERP RS
3.0
Varity_R
0.037
gMVP
0.38

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.

Other links and lift over

dbSNP: rs142417837; hg19: chr6-39159217; API