11-17387430-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_000525.4(KCNJ11):​c.662G>C​(p.Arg221Pro) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R221G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

KCNJ11
NM_000525.4 missense

Scores

8
8
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.70
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000525.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.876

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KCNJ11NM_000525.4 linkc.662G>C p.Arg221Pro missense_variant Exon 1 of 1 ENST00000339994.5 NP_000516.3 Q14654-1B2RC52
KCNJ11NM_001166290.2 linkc.401G>C p.Arg134Pro missense_variant Exon 2 of 2 NP_001159762.1 Q14654-2A0A804HHV7
KCNJ11NM_001377296.1 linkc.401G>C p.Arg134Pro missense_variant Exon 3 of 3 NP_001364225.1
KCNJ11NM_001377297.1 linkc.401G>C p.Arg134Pro missense_variant Exon 2 of 2 NP_001364226.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KCNJ11ENST00000339994.5 linkc.662G>C p.Arg221Pro missense_variant Exon 1 of 1 6 NM_000525.4 ENSP00000345708.4 Q14654-1

Frequencies

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

ClinVar

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

Submissions by phenotype

not provided Uncertain:1
Feb 06, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KCNJ11 protein function. This variant has not been reported in the literature in individuals affected with KCNJ11-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 221 of the KCNJ11 protein (p.Arg221Pro). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.97
BayesDel_addAF
Pathogenic
0.48
D
BayesDel_noAF
Pathogenic
0.46
CADD
Pathogenic
27
DANN
Uncertain
1.0
Eigen
Pathogenic
0.75
Eigen_PC
Pathogenic
0.69
FATHMM_MKL
Uncertain
0.86
D
LIST_S2
Uncertain
0.95
D;.;D
M_CAP
Uncertain
0.23
D
MetaRNN
Pathogenic
0.88
D;D;D
MetaSVM
Pathogenic
0.99
D
PrimateAI
Uncertain
0.57
T
PROVEAN
Uncertain
-4.2
D;D;D
REVEL
Pathogenic
0.88
Sift
Uncertain
0.0010
D;D;D
Sift4G
Uncertain
0.0020
D;D;.
Vest4
0.58
MutPred
0.66
Loss of MoRF binding (P = 0.019);.;.;
MVP
0.99
MPC
1.8
ClinPred
1.0
D
GERP RS
5.3
gMVP
0.99

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: chr11-17408977; API