chr11-17387124-T-TC

Position:

• chr11-17387124-T-TC

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_000525.4(KCNJ11):​c.967_968insG​(p.Asp323GlyfsTer28) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. D323D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNJ11 NM_000525.4 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 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.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 14 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-17387124-T-TC is Pathogenic according to our data. Variant chr11-17387124-T-TC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 478917.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNJ11	NM_000525.4	c.967_968insG	p.Asp323GlyfsTer28	frameshift_variant	1/1	ENST00000339994.5
KCNJ11	NM_001166290.2	c.706_707insG	p.Asp236GlyfsTer28	frameshift_variant	2/2
KCNJ11	NM_001377296.1	c.706_707insG	p.Asp236GlyfsTer28	frameshift_variant	3/3
KCNJ11	NM_001377297.1	c.706_707insG	p.Asp236GlyfsTer28	frameshift_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNJ11	ENST00000339994.5	c.967_968insG	p.Asp323GlyfsTer28	frameshift_variant	1/1		NM_000525.4	P1
KCNJ11	ENST00000528731.1	c.706_707insG	p.Asp236GlyfsTer28	frameshift_variant	2/2	1
KCNJ11	ENST00000682350.1	c.706_707insG	p.Asp236GlyfsTer28	frameshift_variant	2/2
KCNJ11	ENST00000682764.1	c.706_707insG	p.Asp236GlyfsTer28	frameshift_variant	2/3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 67

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Type 2 diabetes mellitus;C4225365:Maturity-onset diabetes of the young type 13 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Shenzhen Institute of Pediatrics, Shenzhen Children's Hospital

Aug 31, 2017

- -

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 with Neonatal Diabetes. However, no sufficient evidence is found to ascertain the role of rs1554901596 variant in MODY yet. -

Computational scores

Source: dbNSFP v4.3

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: rs1554901596; hg19: chr11-17408671;