rs5215

Positions:

• chr11-17387083-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000525.4(KCNJ11):​c.1009G>A​(p.Val337Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.648 in 1,613,990 control chromosomes in the GnomAD database, including 342,278 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.71 (39353 hom., cov: 34)
  • Exomes 𝑓: 0.64 (302925 hom.)
• Consequence: KCNJ11 NM_000525.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14 O:1
• Conservation: PhyloP100: -0.120

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 -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 7 uncertain in NM_000525.4
• BP4: Computational evidence support a benign effect (MetaRNN=8.4797284E-7).
• BP6: Variant 11-17387083-C-T is Benign according to our data. Variant chr11-17387083-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 158670.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-17387083-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.903 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNJ11	NM_000525.4	c.1009G>A	p.Val337Ile	missense_variant	1/1	ENST00000339994.5
KCNJ11	NM_001166290.2	c.748G>A	p.Val250Ile	missense_variant	2/2
KCNJ11	NM_001377296.1	c.748G>A	p.Val250Ile	missense_variant	3/3
KCNJ11	NM_001377297.1	c.748G>A	p.Val250Ile	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNJ11	ENST00000339994.5	c.1009G>A	p.Val337Ile	missense_variant	1/1		NM_000525.4	P1
KCNJ11	ENST00000528731.1	c.748G>A	p.Val250Ile	missense_variant	2/2	1
KCNJ11	ENST00000682350.1	c.748G>A	p.Val250Ile	missense_variant	2/2
KCNJ11	ENST00000682764.1	c.748G>A	p.Val250Ile	missense_variant	2/3

Frequencies

GnomAD3 genomes AF: 0.708 AC: 107545 AN: 152006 Hom.: 39303 Cov.: 34

Gnomad AFR AF: 0.911

Gnomad AMI AF: 0.482

Gnomad AMR AF: 0.670

Gnomad ASJ AF: 0.645

Gnomad EAS AF: 0.646

Gnomad SAS AF: 0.625

Gnomad FIN AF: 0.531

Gnomad MID AF: 0.697

Gnomad NFE AF: 0.637

Gnomad OTH AF: 0.687

GnomAD3 exomes AF: 0.638 AC: 160506 AN: 251456 Hom.: 52127 AF XY: 0.634 AC XY: 86160 AN XY: 135914

Gnomad AFR exome AF: 0.916

Gnomad AMR exome AF: 0.618

Gnomad ASJ exome AF: 0.637

Gnomad EAS exome AF: 0.635

Gnomad SAS exome AF: 0.629

Gnomad FIN exome AF: 0.522

Gnomad NFE exome AF: 0.630

Gnomad OTH exome AF: 0.635

GnomAD4 exome AF: 0.641 AC: 937700 AN: 1461864 Hom.: 302925 Cov.: 73 AF XY: 0.639 AC XY: 464957 AN XY: 727236

Gnomad4 AFR exome AF: 0.924

Gnomad4 AMR exome AF: 0.623

Gnomad4 ASJ exome AF: 0.641

Gnomad4 EAS exome AF: 0.633

Gnomad4 SAS exome AF: 0.630

Gnomad4 FIN exome AF: 0.523

Gnomad4 NFE exome AF: 0.639

Gnomad4 OTH exome AF: 0.654

GnomAD4 genome AF: 0.708 AC: 107657 AN: 152126 Hom.: 39353 Cov.: 34 AF XY: 0.702 AC XY: 52184 AN XY: 74352

Gnomad4 AFR AF: 0.911

Gnomad4 AMR AF: 0.670

Gnomad4 ASJ AF: 0.645

Gnomad4 EAS AF: 0.647

Gnomad4 SAS AF: 0.625

Gnomad4 FIN AF: 0.531

Gnomad4 NFE AF: 0.637

Gnomad4 OTH AF: 0.686

Alfa AF: 0.650 Hom.: 69523

Bravo AF: 0.722

TwinsUK AF: 0.650 AC: 2410

ALSPAC AF: 0.637 AC: 2456

ESP6500AA AF: 0.913 AC: 4018

ESP6500EA AF: 0.639 AC: 5488

ExAC AF: 0.645 AC: 78262

Asia WGS AF: 0.663 AC: 2305 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 02, 2021	- -

Diabetes mellitus, transient neonatal, 3 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jul 01, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 10, 2018	This variant is associated with the following publications: (PMID: 31118516, 30389748, 26551672, 27398621, 17257281, 22958899) -

Hyperinsulinemic hypoglycemia, familial, 2 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jul 01, 2021	- -

Diabetes mellitus, permanent neonatal 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Pars Genome Lab

Jul 01, 2021

- -

Permanent neonatal diabetes mellitus Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Maturity-onset diabetes of the young type 13 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Type 2 diabetes mellitus Other:1

association, no assertion criteria provided

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

-

Mutations can cause decreased production of insulin and secretion. This can lead to MODY which is responsive to oral sulfonylureas. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	8.3
DANN	Benign	0.93
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.070	N
LIST_S2	Benign	0.48	T;.
MetaRNN	Benign	8.5e-7	T;T
MetaSVM	Benign	-0.82	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.10	N;N
REVEL	Benign	0.27
Sift	Benign	0.15	T;T
Sift4G	Benign	0.20	T;T
Vest4		0.017
MPC		0.51
ClinPred		0.0052	T
GERP RS		-6.0
gMVP		0.22

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: rs5215; hg19: chr11-17408630; COSMIC: COSV60595714; COSMIC: COSV60595714;