rs5218

Positions:

• chr11-17387522-G-A
• chr11-17387522-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000525.4(KCNJ11):​c.570C>T​(p.Ala190=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.288 in 1,611,284 control chromosomes in the GnomAD database, including 72,074 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (5170 hom., cov: 33)
  • Exomes 𝑓: 0.29 (66904 hom.)
• Consequence: KCNJ11 NM_000525.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.279

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 11-17387522-G-A is Benign according to our data. Variant chr11-17387522-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 158680.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.279 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.479 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNJ11	NM_000525.4	c.570C>T	p.Ala190=	synonymous_variant	1/1	ENST00000339994.5	NP_000516.3
KCNJ11	NM_001166290.2	c.309C>T	p.Ala103=	synonymous_variant	2/2		NP_001159762.1
KCNJ11	NM_001377296.1	c.309C>T	p.Ala103=	synonymous_variant	3/3		NP_001364225.1
KCNJ11	NM_001377297.1	c.309C>T	p.Ala103=	synonymous_variant	2/2		NP_001364226.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNJ11	ENST00000339994.5	c.570C>T	p.Ala190=	synonymous_variant	1/1		NM_000525.4	ENSP00000345708	P1

Frequencies

GnomAD3 genomes AF: 0.230 AC: 35011 AN: 152016 Hom.: 5169 Cov.: 33

Gnomad AFR AF: 0.0667

Gnomad AMI AF: 0.285

Gnomad AMR AF: 0.185

Gnomad ASJ AF: 0.197

Gnomad EAS AF: 0.494

Gnomad SAS AF: 0.167

Gnomad FIN AF: 0.349

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.308

Gnomad OTH AF: 0.215

GnomAD3 exomes AF: 0.257 AC: 63365 AN: 246490 Hom.: 9487 AF XY: 0.257 AC XY: 34301 AN XY: 133488

Gnomad AFR exome AF: 0.0605

Gnomad AMR exome AF: 0.142

Gnomad ASJ exome AF: 0.198

Gnomad EAS exome AF: 0.490

Gnomad SAS exome AF: 0.164

Gnomad FIN exome AF: 0.336

Gnomad NFE exome AF: 0.299

Gnomad OTH exome AF: 0.255

GnomAD4 exome AF: 0.294 AC: 429328 AN: 1459150 Hom.: 66904 Cov.: 67 AF XY: 0.290 AC XY: 210455 AN XY: 725796

Gnomad4 AFR exome AF: 0.0562

Gnomad4 AMR exome AF: 0.146

Gnomad4 ASJ exome AF: 0.193

Gnomad4 EAS exome AF: 0.474

Gnomad4 SAS exome AF: 0.165

Gnomad4 FIN exome AF: 0.335

Gnomad4 NFE exome AF: 0.313

Gnomad4 OTH exome AF: 0.277

GnomAD4 genome AF: 0.230 AC: 35014 AN: 152134 Hom.: 5170 Cov.: 33 AF XY: 0.233 AC XY: 17302 AN XY: 74362

Gnomad4 AFR AF: 0.0666

Gnomad4 AMR AF: 0.185

Gnomad4 ASJ AF: 0.197

Gnomad4 EAS AF: 0.495

Gnomad4 SAS AF: 0.167

Gnomad4 FIN AF: 0.349

Gnomad4 NFE AF: 0.308

Gnomad4 OTH AF: 0.216

Alfa AF: 0.269 Hom.: 4313

Bravo AF: 0.210

Asia WGS AF: 0.292 AC: 1011 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 17, 2018	This variant is associated with the following publications: (PMID: 14871556, 29396286, 17327377, 17823772, 22916062, 22512215, 28460053, 21573802, 24018988, 1731660, 17727257, 16429405, 11310586, 26740944, 15115830, 24068186, 21765448, 25725792, 17257281, 14551916, 18290324) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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	Athena Diagnostics	Apr 28, 2017	- -

Diabetes mellitus, transient neonatal, 3 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. -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	4.5
DANN	Benign	0.90

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: rs5218; hg19: chr11-17409069; COSMIC: COSV60594603; COSMIC: COSV60594603;