11-128912107-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PP3_Strong

The NM_000890.5(KCNJ5):​c.834T>G​(p.His278Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,366 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. H278H) has been classified as Benign.

Frequency

Genomes: š‘“ 0.000013 ( 0 hom., cov: 33)
Exomes š‘“: 0.0000027 ( 0 hom. )

Consequence

KCNJ5
NM_000890.5 missense

Scores

14
1
4

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.09
Variant links:
Genes affected
KCNJ5 (HGNC:6266): (potassium inwardly rectifying channel subfamily J member 5) This gene encodes an integral membrane protein which belongs to one of seven subfamilies of inward-rectifier potassium channel proteins called potassium channel subfamily J. The encoded protein is a subunit of the potassium channel which is homotetrameric. It is controlled by G-proteins and has a greater tendency to allow potassium to flow into a cell rather than out of a cell. Naturally occurring mutations in this gene are associated with aldosterone-producing adenomas. [provided by RefSeq, Aug 2017]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1
In a topological_domain Cytoplasmic (size 233) in uniprot entity KCNJ5_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_000890.5
PP3
MetaRNN computational evidence supports a deleterious effect, 0.991

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KCNJ5NM_000890.5 linkc.834T>G p.His278Gln missense_variant Exon 2 of 3 ENST00000529694.6 NP_000881.3 P48544A0A5J6E2W8
KCNJ5NM_001354169.2 linkc.834T>G p.His278Gln missense_variant Exon 3 of 4 NP_001341098.1
KCNJ5XM_011542810.4 linkc.834T>G p.His278Gln missense_variant Exon 2 of 3 XP_011541112.1 P48544A0A5J6E2W8

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KCNJ5ENST00000529694.6 linkc.834T>G p.His278Gln missense_variant Exon 2 of 3 1 NM_000890.5 ENSP00000433295.1 P48544
KCNJ5ENST00000338350.4 linkc.834T>G p.His278Gln missense_variant Exon 3 of 4 1 ENSP00000339960.4 P48544
KCNJ5ENST00000533599.1 linkc.834T>G p.His278Gln missense_variant Exon 1 of 2 1 ENSP00000434266.1 P48544

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
152052
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.000577
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000805
AC:
2
AN:
248472
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
134444
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.000200
Gnomad EAS exome
AF:
0.00
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:
0.00000274
AC:
4
AN:
1461314
Hom.:
0
Cov.:
47
AF XY:
0.00000138
AC XY:
1
AN XY:
726928
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.0000765
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000132
AC:
2
AN:
152052
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74282
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.000577
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000284
Hom.:
11998

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.47
D
BayesDel_noAF
Pathogenic
0.44
CADD
Benign
16
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.98
D;D;D
Eigen
Benign
0.081
Eigen_PC
Benign
-0.15
FATHMM_MKL
Benign
0.27
N
LIST_S2
Pathogenic
1.0
.;.;D
M_CAP
Pathogenic
0.87
D
MetaRNN
Pathogenic
0.99
D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.2
H;H;H
PrimateAI
Pathogenic
0.79
T
PROVEAN
Pathogenic
-7.5
D;D;D
REVEL
Pathogenic
0.88
Sift
Pathogenic
0.0
D;D;D
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
1.0
D;D;D
Vest4
0.94
MutPred
0.95
Loss of catalytic residue at I276 (P = 0.1029);Loss of catalytic residue at I276 (P = 0.1029);Loss of catalytic residue at I276 (P = 0.1029);
MVP
0.98
MPC
1.3
ClinPred
1.0
D
GERP RS
-0.73
Varity_R
0.95
gMVP
0.95

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: rs7118833; hg19: chr11-128782002; API