rs193929358

Variant names:

• chr11-17387091-C-A
• NM_000525.4:c.1001G>T

Your query was ambiguous. Multiple possible variants found:

• chr11-17387091-C-A
• chr11-17387091-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Moderate PP5_Moderate

The NM_000525.4(KCNJ11):​c.1001G>T​(p.Gly334Val) 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G334R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNJ11 NM_000525.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P: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 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-17387092-C-G is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.937
• PP5: Variant 11-17387091-C-A is Pathogenic according to our data. Variant chr11-17387091-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1526000.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.1001G>T	p.Gly334Val	missense_variant	Exon 1 of 1	ENST00000339994.5	NP_000516.3
KCNJ11	NM_001166290.2	c.740G>T	p.Gly247Val	missense_variant	Exon 2 of 2		NP_001159762.1
KCNJ11	NM_001377296.1	c.740G>T	p.Gly247Val	missense_variant	Exon 3 of 3		NP_001364225.1
KCNJ11	NM_001377297.1	c.740G>T	p.Gly247Val	missense_variant	Exon 2 of 2		NP_001364226.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNJ11	ENST00000339994.5	c.1001G>T	p.Gly334Val	missense_variant	Exon 1 of 1	6	NM_000525.4	ENSP00000345708.4
KCNJ11	ENST00000528731.1	c.740G>T	p.Gly247Val	missense_variant	Exon 2 of 2	1		ENSP00000434755.1
KCNJ11	ENST00000682350.1	c.740G>T	p.Gly247Val	missense_variant	Exon 2 of 2			ENSP00000508090.1
KCNJ11	ENST00000682764.1	c.740G>T	p.Gly247Val	missense_variant	Exon 2 of 3			ENSP00000506780.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 67

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neonatal diabetes mellitus Pathogenic:1

-

Molecular Genetics, Madras Diabetes Research Foundation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D;.
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Pathogenic	0.91	D
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-4.0	D;D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.011	D;D
Vest4		0.98
MutPred		0.66		Loss of ubiquitination at K332 (P = 0.0505);.;
MVP		0.99
MPC		1.8
ClinPred		1.0	D
GERP RS		5.4
gMVP		0.84

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: chr11-17408638;