rs28936678

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5

The NM_000525.4(KCNJ11):ā€‹c.440T>Cā€‹(p.Leu147Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,726 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 0.0000027 ( 0 hom. )

Consequence

KCNJ11
NM_000525.4 missense

Scores

4
9
4

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1

Conservation

PhyloP100: 3.94
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 7 ACMG points.

PM1
In a helix (size 28) in uniprot entity KCJ11_HUMAN there are 11 pathogenic changes around while only 2 benign (85%) in NM_000525.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.929
PP5
Variant 11-17387652-A-G is Pathogenic according to our data. Variant chr11-17387652-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 8665.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
KCNJ11NM_000525.4 linkuse as main transcriptc.440T>C p.Leu147Pro missense_variant 1/1 ENST00000339994.5
KCNJ11NM_001166290.2 linkuse as main transcriptc.179T>C p.Leu60Pro missense_variant 2/2
KCNJ11NM_001377296.1 linkuse as main transcriptc.179T>C p.Leu60Pro missense_variant 3/3
KCNJ11NM_001377297.1 linkuse as main transcriptc.179T>C p.Leu60Pro missense_variant 2/2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
KCNJ11ENST00000339994.5 linkuse as main transcriptc.440T>C p.Leu147Pro missense_variant 1/1 NM_000525.4 P1Q14654-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000399
AC:
1
AN:
250858
Hom.:
0
AF XY:
0.00000737
AC XY:
1
AN XY:
135664
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000882
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461726
Hom.:
0
Cov.:
63
AF XY:
0.00000275
AC XY:
2
AN XY:
727156
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000360
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Alfa
AF:
0.00210
Hom.:
0
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Hyperinsulinemic hypoglycemia, familial, 2 Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingCenter of Genomic medicine, Geneva, University Hospital of GenevaMar 16, 2015This recessive mutation in the KCNJ11 gene was found in a case of congenital hyperinsulinemic hypoglycemia. The combination of this mutation with a second recessive mutation (c.154C>T) in the same gene explains the phenotype of this newborn patient. -
Pathogenic, no assertion criteria providedliterature onlyOMIMFeb 01, 1995- -
Maturity onset diabetes mellitus in young Uncertain:1
Uncertain significance, criteria provided, single submitterresearchClinical Genomics, Uppaluri K&H Personalized Medicine Clinic-Mutations in KCNJ11 gene can cause decreased production and secretion of insulin. This can lead to MODY which may be responsive to oral sulfonylureas. However, no sufficient evidence is found to ascertain the role of this particular variant (rs28936678 ) in MODY yet. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.49
BayesDel_addAF
Pathogenic
0.46
D
BayesDel_noAF
Pathogenic
0.42
CADD
Uncertain
25
DANN
Uncertain
1.0
Eigen
Benign
0.15
Eigen_PC
Benign
0.21
FATHMM_MKL
Uncertain
0.81
D
LIST_S2
Uncertain
0.94
D;.;D
M_CAP
Uncertain
0.12
D
MetaRNN
Pathogenic
0.93
D;D;D
MetaSVM
Benign
-0.87
T
MutationTaster
Benign
1.0
A;A
PrimateAI
Uncertain
0.72
T
PROVEAN
Uncertain
-3.2
D;D;D
REVEL
Pathogenic
0.88
Sift
Uncertain
0.0070
D;D;D
Sift4G
Uncertain
0.0080
D;D;.
Vest4
0.94
MutPred
0.83
Loss of stability (P = 0.0083);.;.;
MVP
0.95
MPC
1.9
ClinPred
0.94
D
GERP RS
4.9
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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs28936678; hg19: chr11-17409199; API