11-17386938-G-C

Variant names:

• chr11-17386938-G-C
• rs41282930
• NM_000525.4:c.1154C>G

Variant summary

Our verdict is Benign. The variant received -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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S385F) has been classified as Uncertain significance.

• 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
• Publications: 26 publications found

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]

KCNJ11 Gene-Disease associations (from GenCC):

• diabetes mellitus, transient neonatal, 3

  Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• monogenic diabetes

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hyperinsulinemic hypoglycemia, familial, 2

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Genomics England PanelApp
• diabetes mellitus, noninsulin-dependent

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• diabetes mellitus, permanent neonatal 2

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• maturity-onset diabetes of the young type 13

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• autosomal dominant hyperinsulinism due to Kir6.2 deficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• DEND syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• intermediate DEND syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• maturity-onset diabetes of the young

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• permanent neonatal diabetes mellitus

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• transient neonatal diabetes mellitus

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive hyperinsulinism due to Kir6.2 deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• diazoxide-resistant focal hyperinsulinism due to Kir6.2 deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 36430.
• 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 the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 21 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000525.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNJ11	NM_000525.4	MANE Select	c.1154C>G	p.Ser385Cys	missense	Exon 1 of 1	NP_000516.3
	KCNJ11	NM_001166290.2		c.893C>G	p.Ser298Cys	missense	Exon 2 of 2	NP_001159762.1	A0A804HHV7
	KCNJ11	NM_001377296.1		c.893C>G	p.Ser298Cys	missense	Exon 3 of 3	NP_001364225.1	A0A804HHV7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNJ11	ENST00000339994.5	TSL:6 MANE Select	c.1154C>G	p.Ser385Cys	missense	Exon 1 of 1	ENSP00000345708.4	Q14654-1
	KCNJ11	ENST00000528731.1	TSL:1	c.893C>G	p.Ser298Cys	missense	Exon 2 of 2	ENSP00000434755.1	Q14654-2
	KCNJ11	ENST00000948565.1		c.1154C>G	p.Ser385Cys	missense	Exon 2 of 2	ENSP00000618624.1

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

GnomAD2 exomes AF: 0.00456 AC: 1141 AN: 250126 AF XY: 0.00447

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 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

African (AFR) AF: 0.0253 AC: 848 AN: 33460

American (AMR) AF: 0.00378 AC: 169 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 262 AN: 26026

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39686

South Asian (SAS) AF: 0.00548 AC: 472 AN: 86096

European-Finnish (FIN) AF: 0.000188 AC: 10 AN: 53226

Middle Eastern (MID) AF: 0.0245 AC: 141 AN: 5758

European-Non Finnish (NFE) AF: 0.00236 AC: 2622 AN: 1111464

Other (OTH) AF: 0.00590 AC: 356 AN: 60342

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

African (AFR) AF: 0.0246 AC: 1022 AN: 41586

American (AMR) AF: 0.00849 AC: 130 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.0118 AC: 41 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5170

South Asian (SAS) AF: 0.00331 AC: 16 AN: 4830

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10626

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.00276 AC: 188 AN: 68032

Other (OTH) AF: 0.0133 AC: 28 AN: 2110

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

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	1	1	Hyperinsulinemic hypoglycemia, familial, 2 (2)
-	-	2	not specified (2)
-	-	1	Diabetes mellitus, transient neonatal, 3 (1)
-	1	-	Maturity-onset diabetes of the young (1)
-	-	1	Maturity-onset diabetes of the young type 13 (1)
-	-	1	Monogenic diabetes (1)
-	-	1	Neonatal diabetes mellitus (1)

Computational scores

Source: dbNSFP v4.9

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
MetaSVM	Uncertain	0.18	D
PhyloP100		3.1
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.37
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0090	D
Vest4		0.17
MVP		0.96
MPC		0.81
ClinPred		0.017	T
GERP RS		5.2
gMVP		0.48
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs41282930; hg19: chr11-17408485;