11-17386938-G-C

Position:

• chr11-17386938-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000525.4(KCNJ11):​c.1154C>G​(p.Ser385Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00392 in 1,613,062 control chromosomes in the GnomAD database, including 54 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 0.0094 (21 hom., cov: 34)
  • Exomes 𝑓: 0.0033 (33 hom.)
• Consequence: KCNJ11 NM_000525.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:10
• Conservation: PhyloP100: 3.07

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005117476).
• BP6: Variant 11-17386938-G-C is Benign according to our data. Variant chr11-17386938-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 36430.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2, Benign=8}. Variant chr11-17386938-G-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00945 (1439/152342) while in subpopulation AFR AF= 0.0246 (1022/41586). AF 95% confidence interval is 0.0233. There are 21 homozygotes in gnomad4. There are 680 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.1154C>G	p.Ser385Cys	missense_variant	1/1	ENST00000339994.5	NP_000516.3
KCNJ11	NM_001166290.2	c.893C>G	p.Ser298Cys	missense_variant	2/2		NP_001159762.1
KCNJ11	NM_001377296.1	c.893C>G	p.Ser298Cys	missense_variant	3/3		NP_001364225.1
KCNJ11	NM_001377297.1	c.893C>G	p.Ser298Cys	missense_variant	2/2		NP_001364226.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNJ11	ENST00000339994.5	c.1154C>G	p.Ser385Cys	missense_variant	1/1	6	NM_000525.4	ENSP00000345708.4
KCNJ11	ENST00000528731.1	c.893C>G	p.Ser298Cys	missense_variant	2/2	1		ENSP00000434755.1
KCNJ11	ENST00000682350.1	c.893C>G	p.Ser298Cys	missense_variant	2/2			ENSP00000508090.1
KCNJ11	ENST00000682764.1	c.893C>G	p.Ser298Cys	missense_variant	2/3			ENSP00000506780.1

Frequencies

GnomAD3 genomes AF: 0.00943 AC: 1436 AN: 152224 Hom.: 21 Cov.: 34

Gnomad AFR AF: 0.0246

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00850

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.00276

Gnomad OTH AF: 0.0134

GnomAD3 exomes AF: 0.00456 AC: 1141 AN: 250126 Hom.: 9 AF XY: 0.00447 AC XY: 604 AN XY: 135252

Gnomad AFR exome AF: 0.0241

Gnomad AMR exome AF: 0.00330

Gnomad ASJ exome AF: 0.0102

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00516

Gnomad FIN exome AF: 0.0000930

Gnomad NFE exome AF: 0.00310

Gnomad OTH exome AF: 0.00410

GnomAD4 exome AF: 0.00334 AC: 4884 AN: 1460720 Hom.: 33 Cov.: 32 AF XY: 0.00343 AC XY: 2491 AN XY: 726558

Gnomad4 AFR exome AF: 0.0253

Gnomad4 AMR exome AF: 0.00378

Gnomad4 ASJ exome AF: 0.0101

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00548

Gnomad4 FIN exome AF: 0.000188

Gnomad4 NFE exome AF: 0.00236

Gnomad4 OTH exome AF: 0.00590

GnomAD4 genome AF: 0.00945 AC: 1439 AN: 152342 Hom.: 21 Cov.: 34 AF XY: 0.00913 AC XY: 680 AN XY: 74494

Gnomad4 AFR AF: 0.0246

Gnomad4 AMR AF: 0.00849

Gnomad4 ASJ AF: 0.0118

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00331

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00276

Gnomad4 OTH AF: 0.0133

Alfa AF: 0.00501 Hom.: 1

Bravo AF: 0.0107

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.0227 AC: 100

ESP6500EA AF: 0.00373 AC: 32

ExAC AF: 0.00480 AC: 583

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.00431

EpiControl AF: 0.00421

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 22, 2021	This variant is associated with the following publications: (PMID: 22289434, 21968738, 24068186, 21119644, 25998140, 24698822, 28460053, 31149081, 25247988, 28587604, 8897013, 10338089, 15504982, 15115830, 29396286) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 01, 2017	- -

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

Likely benign, criteria provided, single submitter	clinical testing	Pars Genome 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 specified Benign:2

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	Oct 17, 2013	- -

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 Neonatal Diabetes. However, no sufficient evidence is found to ascertain the role of rs41282930 variant in Diabetes Mellitus yet. -

Neonatal diabetes mellitus Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 18, 2011

- -

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. -

Monogenic diabetes Benign:1

Benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Feb 22, 2019

ACMG criteria: BA1 (2.4% in Africans in gnomAD) + BS2 (125 controls and 75 cases in T2D) (removed BP4 because of conflicting evidence: BP4 [4 predictors]; PP3 [6 predictors], REVEL=0.369)=benign -

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
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	23
DANN	Uncertain	0.98
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.72	T;.
MetaRNN	Benign	0.0051	T;T
MetaSVM	Uncertain	0.18	D
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.7	N;N
REVEL	Uncertain	0.37
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0090	D;D
Vest4		0.17
MVP		0.96
MPC		0.81
ClinPred		0.017	T
GERP RS		5.2
gMVP		0.48

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: rs41282930; hg19: chr11-17408485;