chr11-17387226-C-G

Position:

• chr11-17387226-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000525.4(KCNJ11):​c.866G>C​(p.Gly289Ala) 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNJ11 NM_000525.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U: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 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• PP5: Variant 11-17387226-C-G is Pathogenic according to our data. Variant chr11-17387226-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 211228.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1}. Variant chr11-17387226-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNJ11	NM_000525.4	c.866G>C	p.Gly289Ala	missense_variant	1/1	ENST00000339994.5	NP_000516.3
KCNJ11	NM_001166290.2	c.605G>C	p.Gly202Ala	missense_variant	2/2		NP_001159762.1
KCNJ11	NM_001377296.1	c.605G>C	p.Gly202Ala	missense_variant	3/3		NP_001364225.1
KCNJ11	NM_001377297.1	c.605G>C	p.Gly202Ala	missense_variant	2/2		NP_001364226.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNJ11	ENST00000339994.5	c.866G>C	p.Gly289Ala	missense_variant	1/1		NM_000525.4	ENSP00000345708	P1
KCNJ11	ENST00000528731.1	c.605G>C	p.Gly202Ala	missense_variant	2/2	1		ENSP00000434755
KCNJ11	ENST00000682350.1	c.605G>C	p.Gly202Ala	missense_variant	2/2			ENSP00000508090
KCNJ11	ENST00000682764.1	c.605G>C	p.Gly202Ala	missense_variant	2/3			ENSP00000506780

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 68

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Type 2 diabetes mellitus Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jun 19, 2023

- -

Hyperinsulinemic hypoglycemia, familial, 2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 09, 2015

- -

Maturity onset diabetes mellitus in young Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Clinical 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. It is also associated with Neonatal Diabetes. However, no sufficient evidence is found to ascertain the role of rs797045637 variant in MODY yet. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.50
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;.
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	0.99	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-5.7	D;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.023	D;T
Vest4		0.91
MutPred		0.92		Gain of sheet (P = 0.0827);.;
MVP		0.93
MPC		1.7
ClinPred		1.0	D
GERP RS		5.4
gMVP		0.89

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: rs797045637; hg19: chr11-17408773;