chr11-17387935-C-G

Position:

• chr11-17387935-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000525.4(KCNJ11):​c.157G>C​(p.Gly53Arg) 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 (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNJ11 NM_000525.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P: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 9 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, 0.97
• PP5: Variant 11-17387935-C-G is Pathogenic according to our data. Variant chr11-17387935-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 8682.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNJ11	NM_000525.4	c.157G>C	p.Gly53Arg	missense_variant	1/1	ENST00000339994.5	NP_000516.3
KCNJ11	NM_001166290.2	c.-16-89G>C		intron_variant			NP_001159762.1
KCNJ11	NM_001377296.1	c.-17+83G>C		intron_variant			NP_001364225.1
KCNJ11	NM_001377297.1	c.-16-89G>C		intron_variant			NP_001364226.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNJ11	ENST00000339994.5	c.157G>C	p.Gly53Arg	missense_variant	1/1		NM_000525.4	ENSP00000345708	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 63

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Diabetes mellitus, transient neonatal, 3 Pathogenic:1 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2005	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Benign	-0.68	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	-2.0	N
REVEL	Pathogenic	0.82
Sift	Benign	0.45	T
Sift4G	Benign	0.38	T
Vest4		0.95
MutPred		0.94		Gain of MoRF binding (P = 0.034);
MVP		0.98
MPC		1.8
ClinPred		0.96	D
GERP RS		4.6
gMVP		0.93

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: rs80356613; hg19: chr11-17409482;