rs8175351

Positions:

• chr11-17386949-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_000525.4(KCNJ11):​c.1143G>A​(p.Lys381Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0181 in 1,613,174 control chromosomes in the GnomAD database, including 358 homozygotes. 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 0.013 (21 hom., cov: 34)
  • Exomes 𝑓: 0.019 (337 hom.)
• Consequence: KCNJ11 NM_000525.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:12
• Conservation: PhyloP100: 0.818

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 11-17386949-C-T is Benign according to our data. Variant chr11-17386949-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 158672.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=9}. Variant chr11-17386949-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.818 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0127 (1937/152300) while in subpopulation NFE AF= 0.021 (1429/68004). AF 95% confidence interval is 0.0201. There are 21 homozygotes in gnomad4. There are 853 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 21 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNJ11	NM_000525.4	c.1143G>A	p.Lys381Lys	synonymous_variant	1/1	ENST00000339994.5	NP_000516.3
KCNJ11	NM_001166290.2	c.882G>A	p.Lys294Lys	synonymous_variant	2/2		NP_001159762.1
KCNJ11	NM_001377296.1	c.882G>A	p.Lys294Lys	synonymous_variant	3/3		NP_001364225.1
KCNJ11	NM_001377297.1	c.882G>A	p.Lys294Lys	synonymous_variant	2/2		NP_001364226.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNJ11	ENST00000339994.5	c.1143G>A	p.Lys381Lys	synonymous_variant	1/1	6	NM_000525.4	ENSP00000345708.4
KCNJ11	ENST00000528731.1	c.882G>A	p.Lys294Lys	synonymous_variant	2/2	1		ENSP00000434755.1
KCNJ11	ENST00000682350.1	c.882G>A	p.Lys294Lys	synonymous_variant	2/2			ENSP00000508090.1
KCNJ11	ENST00000682764.1	c.882G>A	p.Lys294Lys	synonymous_variant	2/3			ENSP00000506780.1

Frequencies

GnomAD3 genomes AF: 0.0127 AC: 1938 AN: 152182 Hom.: 21 Cov.: 34

Gnomad AFR AF: 0.00432

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0102

Gnomad ASJ AF: 0.0207

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00517

Gnomad FIN AF: 0.00292

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0210

Gnomad OTH AF: 0.0186

GnomAD3 exomes AF: 0.0126 AC: 3147 AN: 250258 Hom.: 39 AF XY: 0.0126 AC XY: 1703 AN XY: 135312

Gnomad AFR exome AF: 0.00376

Gnomad AMR exome AF: 0.00800

Gnomad ASJ exome AF: 0.0199

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00542

Gnomad FIN exome AF: 0.00465

Gnomad NFE exome AF: 0.0199

Gnomad OTH exome AF: 0.0156

GnomAD4 exome AF: 0.0186 AC: 27239 AN: 1460874 Hom.: 337 Cov.: 32 AF XY: 0.0183 AC XY: 13305 AN XY: 726644

Gnomad4 AFR exome AF: 0.00374

Gnomad4 AMR exome AF: 0.00871

Gnomad4 ASJ exome AF: 0.0210

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00538

Gnomad4 FIN exome AF: 0.00546

Gnomad4 NFE exome AF: 0.0218

Gnomad4 OTH exome AF: 0.0170

GnomAD4 genome AF: 0.0127 AC: 1937 AN: 152300 Hom.: 21 Cov.: 34 AF XY: 0.0115 AC XY: 853 AN XY: 74490

Gnomad4 AFR AF: 0.00430

Gnomad4 AMR AF: 0.0101

Gnomad4 ASJ AF: 0.0207

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00518

Gnomad4 FIN AF: 0.00292

Gnomad4 NFE AF: 0.0210

Gnomad4 OTH AF: 0.0184

Alfa AF: 0.0197 Hom.: 47

Bravo AF: 0.0129

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.0230

EpiControl AF: 0.0202

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:12

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -

Hyperinsulinemic hypoglycemia, familial, 2 Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 19, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 24, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 08, 2021	This variant is associated with the following publications: (PMID: 16429405, 17316607, 15504982) -

Hyperinsulinemia 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, significance of rs8175351 is uncertain in Hyperinsulinemic Hypoglycemia of Infancy. -

Diabetes mellitus, transient neonatal, 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	8.8
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: rs8175351; hg19: chr11-17408496;