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rs80356624

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong

The NM_000525.4(KCNJ11):c.602G>T(p.Arg201Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 11/18 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R201C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

KCNJ11
NM_000525.4 missense

Scores

14
2
1

Clinical Significance

not provided no classification provided O:1

Conservation

PhyloP100: 7.91
Variant links:
Genes affected
KCNJ11 (HGNC:6257): (potassium inwardly rectifying channel subfamily J member 11) Potassium channels are present in most mammalian cells, where they participate in a wide range of physiologic responses. The protein encoded by this gene is an integral membrane protein and inward-rectifier type potassium channel. The encoded protein, which has a greater tendency to allow potassium to flow into a cell rather than out of a cell, is controlled by G-proteins and is found associated with the sulfonylurea receptor SUR. Mutations in this gene are a cause of familial persistent hyperinsulinemic hypoglycemia of infancy (PHHI), an autosomal recessive disorder characterized by unregulated insulin secretion. Defects in this gene may also contribute to autosomal dominant non-insulin-dependent diabetes mellitus type II (NIDDM), transient neonatal diabetes mellitus type 3 (TNDM3), and permanent neonatal diabetes mellitus (PNDM). Multiple alternatively spliced transcript variants that encode different protein isoforms have been described for this gene. [provided by RefSeq, Oct 2009]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_000525.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr11-17387490-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 8666.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=8, not_provided=1, Uncertain_significance=1}.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.993

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
KCNJ11NM_000525.4 linkuse as main transcriptc.602G>T p.Arg201Leu missense_variant 1/1 ENST00000339994.5
KCNJ11NM_001166290.2 linkuse as main transcriptc.341G>T p.Arg114Leu missense_variant 2/2
KCNJ11NM_001377296.1 linkuse as main transcriptc.341G>T p.Arg114Leu missense_variant 3/3
KCNJ11NM_001377297.1 linkuse as main transcriptc.341G>T p.Arg114Leu missense_variant 2/2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
KCNJ11ENST00000339994.5 linkuse as main transcriptc.602G>T p.Arg201Leu missense_variant 1/1 NM_000525.4 P1Q14654-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
68
GnomAD4 genome
Cov.:
33

ClinVar

Significance: not provided
Submissions summary: Other:1
Revision: no classification provided
LINK: link

Submissions by phenotype

Permanent neonatal diabetes mellitus Other:1
not provided, no classification providedliterature onlyGeneReviews-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.97
BayesDel_addAF
Pathogenic
0.58
D
BayesDel_noAF
Pathogenic
0.59
Cadd
Pathogenic
26
Dann
Uncertain
1.0
Eigen
Pathogenic
0.94
Eigen_PC
Pathogenic
0.85
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Pathogenic
1.0
D;.;D
M_CAP
Pathogenic
0.68
D
MetaRNN
Pathogenic
0.99
D;D;D
MetaSVM
Pathogenic
1.1
D
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.86
D
PROVEAN
Pathogenic
-6.8
D;D;D
REVEL
Pathogenic
0.99
Sift
Pathogenic
0.0
D;D;D
Sift4G
Pathogenic
0.0010
D;D;.
Vest4
0.96
MutPred
0.98
Loss of MoRF binding (P = 0.0192);.;.;
MVP
0.99
MPC
1.8
ClinPred
1.0
D
GERP RS
5.2
gMVP
1.0

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: rs80356624; hg19: chr11-17409037; API