rs5217

Positions:

• chr11-17387508-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1 BP4_Strong BP6 BS1

The NM_000525.4(KCNJ11):​c.584G>A​(p.Arg195His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000207 in 1,611,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: KCNJ11 NM_000525.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: 1.03

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 Benign. Variant got -7 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 2 uncertain in NM_000525.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.020876676).
• BP6: Variant 11-17387508-C-T is Benign according to our data. Variant chr11-17387508-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 158681.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=1, Uncertain_significance=2}. Variant chr11-17387508-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0012 (182/152264) while in subpopulation AFR AF= 0.00431 (179/41558). AF 95% confidence interval is 0.00379. There are 0 homozygotes in gnomad4. There are 81 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNJ11	NM_000525.4	c.584G>A	p.Arg195His	missense_variant	1/1	ENST00000339994.5
KCNJ11	NM_001166290.2	c.323G>A	p.Arg108His	missense_variant	2/2
KCNJ11	NM_001377296.1	c.323G>A	p.Arg108His	missense_variant	3/3
KCNJ11	NM_001377297.1	c.323G>A	p.Arg108His	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNJ11	ENST00000339994.5	c.584G>A	p.Arg195His	missense_variant	1/1		NM_000525.4	P1

Frequencies

GnomAD3 genomes AF: 0.00119 AC: 181 AN: 152146 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00430

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000291 AC: 72 AN: 247248 Hom.: 0 AF XY: 0.000209 AC XY: 28 AN XY: 133962

Gnomad AFR exome AF: 0.00380

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000102

Gnomad NFE exome AF: 0.00000891

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000104 AC: 152 AN: 1459570 Hom.: 0 Cov.: 67 AF XY: 0.000109 AC XY: 79 AN XY: 726076

Gnomad4 AFR exome AF: 0.00320

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.0000778

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.000282

GnomAD4 genome AF: 0.00120 AC: 182 AN: 152264 Hom.: 0 Cov.: 33 AF XY: 0.00109 AC XY: 81 AN XY: 74432

Gnomad4 AFR AF: 0.00431

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000300 Hom.: 0

Bravo AF: 0.00135

ESP6500AA AF: 0.00364 AC: 16

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000379 AC: 46

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 07, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 06, 2018	This variant is associated with the following publications: (PMID: 21544516, 21119644, 27908292) -

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. However, no sufficient evidence is found to ascertain the role of this particular variant (rs5217) in MODY or Congenital Hyperinsulinism or PNDM yet. -

Permanent neonatal diabetes mellitus;C1864623:Diabetes mellitus, transient neonatal, 3;C2931833:Hyperinsulinemic hypoglycemia, familial, 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Oct 13, 2017

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

KCNJ11-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 03, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Permanent neonatal diabetes mellitus Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	26
DANN	Pathogenic	1.0
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Benign	0.61	D
LIST_S2	Uncertain	0.94	D;.;D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.021	T;T;T
MetaSVM	Uncertain	0.68	D
MutationTaster	Benign	0.72	N;N
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.3	D;D;D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.020	D;D;.
Vest4		0.20
MVP		0.99
MPC		0.78
ClinPred		0.048	T
GERP RS		4.3
gMVP		0.77

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: rs5217; hg19: chr11-17409055;