rs5216

Variant names:

• chr11-17387291-G-C
• rs5216
• NM_000525.4:c.801C>G

Your query was ambiguous. Multiple possible variants found:

• chr11-17387291-G-C
• chr11-17387291-G-A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_000525.4(KCNJ11):​c.801C>G​(p.Leu267Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.021 in 1,614,180 control chromosomes in the GnomAD database, including 405 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 0.016 (24 hom., cov: 33)
  • Exomes 𝑓: 0.022 (381 hom.)
• Consequence: KCNJ11 NM_000525.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:19
• Conservation: PhyloP100: 0.864
• Publications: 21 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 11-17387291-G-C is Benign according to our data. Variant chr11-17387291-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 158684.
• BP7: Synonymous conserved (PhyloP=0.864 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0155 (2365/152290) while in subpopulation NFE AF = 0.0239 (1623/68026). AF 95% confidence interval is 0.0229. There are 24 homozygotes in GnomAd4. There are 1075 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 24 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.801C>G	p.Leu267Leu	synonymous	Exon 1 of 1	NP_000516.3
	KCNJ11	NM_001166290.2		c.540C>G	p.Leu180Leu	synonymous	Exon 2 of 2	NP_001159762.1	A0A804HHV7
	KCNJ11	NM_001377296.1		c.540C>G	p.Leu180Leu	synonymous	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.801C>G	p.Leu267Leu	synonymous	Exon 1 of 1	ENSP00000345708.4	Q14654-1
	KCNJ11	ENST00000528731.1	TSL:1	c.540C>G	p.Leu180Leu	synonymous	Exon 2 of 2	ENSP00000434755.1	Q14654-2
	KCNJ11	ENST00000948565.1		c.801C>G	p.Leu267Leu	synonymous	Exon 2 of 2	ENSP00000618624.1

Frequencies

GnomAD3 genomes AF: 0.0155 AC: 2366 AN: 152172 Hom.: 24 Cov.: 33

Gnomad AFR AF: 0.00499

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0183

Gnomad ASJ AF: 0.00950

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.0190

Gnomad FIN AF: 0.00819

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0239

Gnomad OTH AF: 0.0153

GnomAD2 exomes AF: 0.0169 AC: 4238 AN: 251358 AF XY: 0.0180

Gnomad AFR exome AF: 0.00375

Gnomad AMR exome AF: 0.0120

Gnomad ASJ exome AF: 0.0118

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00841

Gnomad NFE exome AF: 0.0232

Gnomad OTH exome AF: 0.0164

GnomAD4 exome AF: 0.0215 AC: 31464 AN: 1461890 Hom.: 381 Cov.: 67 AF XY: 0.0216 AC XY: 15698 AN XY: 727246

African (AFR) AF: 0.00472 AC: 158 AN: 33480

American (AMR) AF: 0.0122 AC: 546 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0115 AC: 301 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0224 AC: 1931 AN: 86258

European-Finnish (FIN) AF: 0.00942 AC: 503 AN: 53418

Middle Eastern (MID) AF: 0.0276 AC: 159 AN: 5768

European-Non Finnish (NFE) AF: 0.0240 AC: 26692 AN: 1112010

Other (OTH) AF: 0.0194 AC: 1174 AN: 60396

GnomAD4 genome AF: 0.0155 AC: 2365 AN: 152290 Hom.: 24 Cov.: 33 AF XY: 0.0144 AC XY: 1075 AN XY: 74460

African (AFR) AF: 0.00498 AC: 207 AN: 41568

American (AMR) AF: 0.0182 AC: 279 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00950 AC: 33 AN: 3472

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5154

South Asian (SAS) AF: 0.0191 AC: 92 AN: 4826

European-Finnish (FIN) AF: 0.00819 AC: 87 AN: 10620

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0239 AC: 1623 AN: 68026

Other (OTH) AF: 0.0152 AC: 32 AN: 2112

Alfa AF: 0.0164 Hom.: 4

Bravo AF: 0.0155

Asia WGS AF: 0.0100 AC: 36 AN: 3478

EpiCase AF: 0.0245

EpiControl AF: 0.0243

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	5	not specified (5)
-	1	2	Hyperinsulinemic hypoglycemia, familial, 2 (3)
-	-	2	Diabetes mellitus, transient neonatal, 3 (2)
-	-	1	Diabetes mellitus, permanent neonatal 2 (1)
-	-	1	Hyperinsulinemic hypoglycemia (1)
-	-	1	Maturity-onset diabetes of the young type 13 (1)
-	-	1	Permanent neonatal diabetes mellitus (1)
-	-	1	Type 2 diabetes mellitus (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	4.0
DANN	Benign	0.69
PhyloP100		0.86
Mutation Taster		=93/7	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs5216; hg19: chr11-17408838;