6-39191264-C-G

Variant summary

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

The NM_003740.4(KCNK5):​c.1126G>C​(p.Ala376Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 (★).

Frequency

Genomes: not found (cov: 32)

Consequence

KCNK5
NM_003740.4 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.677
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]

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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=0.09415159).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
KCNK5NM_003740.4 linkuse as main transcriptc.1126G>C p.Ala376Pro missense_variant 5/5 ENST00000359534.4
KCNK5XM_005249456.2 linkuse as main transcriptc.1117G>C p.Ala373Pro missense_variant 5/5
KCNK5XM_006715235.2 linkuse as main transcriptc.580G>C p.Ala194Pro missense_variant 3/3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
KCNK5ENST00000359534.4 linkuse as main transcriptc.1126G>C p.Ala376Pro missense_variant 5/51 NM_003740.4 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

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 GeneticsJan 30, 2024The c.1126G>C (p.A376P) 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 1126, causing the alanine (A) at amino acid position 376 to be replaced by a proline (P). 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
0.082
BayesDel_addAF
Benign
-0.14
T
BayesDel_noAF
Benign
-0.44
CADD
Benign
7.1
DANN
Uncertain
0.98
DEOGEN2
Benign
0.094
T
Eigen
Benign
-0.52
Eigen_PC
Benign
-0.50
FATHMM_MKL
Benign
0.23
N
LIST_S2
Benign
0.39
T
M_CAP
Benign
0.0050
T
MetaRNN
Benign
0.094
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.90
L
MutationTaster
Benign
1.0
N
PrimateAI
Benign
0.33
T
PROVEAN
Benign
-0.51
N
REVEL
Benign
0.15
Sift
Benign
0.28
T
Sift4G
Benign
0.28
T
Polyphen
0.38
B
Vest4
0.21
MutPred
0.19
Gain of loop (P = 0.0051);
MVP
0.54
MPC
1.1
ClinPred
0.49
T
GERP RS
4.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.13
gMVP
0.39

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-39159040; API