rs80356615

Variant names:

• chr11-17387934-C-T
• rs80356615
• NM_000525.4:c.158G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 8P and 2B. PM1 PM2 PP3_Strong BP6_Moderate

The NM_000525.4(KCNJ11):​c.158G>A​(p.Gly53Asp) 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 Benign (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNJ11 NM_000525.4 missense
• Clinical Significance: Benign criteria provided, single submitter P:1 B:1 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 Likely_pathogenic. Variant got 6 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, 0.977
• BP6: Variant 11-17387934-C-T is Benign according to our data. Variant chr11-17387934-C-T is described in ClinVar as [Benign]. Clinvar id is 8685.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.158G>A	p.Gly53Asp	missense_variant	Exon 1 of 1	ENST00000339994.5	NP_000516.3
KCNJ11	NM_001166290.2	c.-16-88G>A		intron_variant	Intron 1 of 1		NP_001159762.1
KCNJ11	NM_001377296.1	c.-17+84G>A		intron_variant	Intron 2 of 2		NP_001364225.1
KCNJ11	NM_001377297.1	c.-16-88G>A		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.158G>A	p.Gly53Asp	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

Alfa AF: 0.00209 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Diabetes mellitus, permanent neonatal 2 Pathogenic:1

Mar 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Neonatal hypoglycemia Benign:1

-

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

Mutations in KCNJ11 gene can cause decreased production and secretion of insulin. This can lead to MODY. However,role of rs80356615 in oral sulfonylureas response remains uncertain. -

Permanent neonatal diabetes mellitus Other:1

-

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	0.86
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Uncertain	26
DANN	Uncertain	1.0
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.96	D
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	-2.3	N
REVEL	Pathogenic	0.84
Sift	Benign	0.15	T
Sift4G	Benign	0.22	T
Vest4		0.95
MutPred		0.93		Loss of MoRF binding (P = 0.0477);
MVP		1.0
MPC		1.8
ClinPred		0.98	D
GERP RS		4.6
gMVP		0.92

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: rs80356615; hg19: chr11-17409481;