11-17387943-C-G

Variant names:

• chr11-17387943-C-G
• rs80356611
• NM_000525.4:c.149G>C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_000525.4(KCNJ11):​c.149G>C​(p.Arg50Pro) 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. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNJ11 NM_000525.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 7.91

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 67) in uniprot entity KCJ11_HUMAN there are 13 pathogenic changes around while only 1 benign (93%) in NM_000525.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant 11-17387943-C-G is Pathogenic according to our data. Variant chr11-17387943-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 8670.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNJ11	NM_000525.4	c.149G>C	p.Arg50Pro	missense_variant	Exon 1 of 1	ENST00000339994.5	NP_000516.3
KCNJ11	NM_001166290.2	c.-16-97G>C		intron_variant	Intron 1 of 1		NP_001159762.1
KCNJ11	NM_001377296.1	c.-17+75G>C		intron_variant	Intron 2 of 2		NP_001364225.1
KCNJ11	NM_001377297.1	c.-16-97G>C		intron_variant	Intron 1 of 1		NP_001364226.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNJ11	ENST00000339994.5	c.149G>C	p.Arg50Pro	missense_variant	Exon 1 of 1	6	NM_000525.4	ENSP00000345708.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 64

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Diabetes mellitus, permanent neonatal 2 Pathogenic:1

Jan 01, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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KCNJ11-related disorder Pathogenic:1

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Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been previously reported as a heterozygous change in patients with developmental delay, epilepsy, and permanent neonatal diabetes (DEND) and isolated permanent neonatal diabetes (PMID: 15580558, 25739471, 25678012, 27681997). The c.149G>C (p.Arg50Pro) variant is located in a mutational hotspot for pathogenic variations associated with neonatal diabetes (PMID: 16731833). Different amino acid changes at the same residue (p.Arg50Gln, p.Arg50Gly, and p.Arg50Trp) have been previously reported in individuals with permanent neonatal diabetes and transient neonatal diabetes (PMID: 17635943, 16609879, 22749773, 32893419, 31291970). Functional studies showed that the p.Arg50 residue lies in the ATP-binding site of the inwardly rectifying potassium channel K(ATP) and reduces ATP sensitivity and leads to an increase in the K(ATP) channel current (PMID: 16731833). The c.149G>C (p.Arg50Pro) variant is absent from the gnomAD population database and thus is presumed to be rare. The c.149G>C (p.Arg50Pro) variant affects a highly conserved amino acid; however, in silico tools used to predict the effect of this variant on protein function yield discordant results. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event.Based on the available evidence, the c.149G>C (p.Arg50Pro) variant is classified as Pathogenic. -

Permanent neonatal diabetes mellitus Other:1

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	30
DANN	Uncertain	1.0
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.89	D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.018	D
Sift4G	Benign	0.20	T
Vest4		0.92
MutPred		0.94		Loss of MoRF binding (P = 0.002);
MVP		1.0
MPC		1.9
ClinPred		0.98	D
GERP RS		4.6
gMVP		0.91

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

Other links and lift over

dbSNP: rs80356611; hg19: chr11-17409490;