rs8175351

Variant names:

• chr11-17386949-C-T
• rs8175351
• NM_000525.4:c.1143G>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.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
• Publications: 13 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=-0.49).
• 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 VariationId is 158672.
• 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 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.1143G>A	p.Lys381Lys	synonymous	Exon 1 of 1	NP_000516.3
	KCNJ11	NM_001166290.2		c.882G>A	p.Lys294Lys	synonymous	Exon 2 of 2	NP_001159762.1	A0A804HHV7
	KCNJ11	NM_001377296.1		c.882G>A	p.Lys294Lys	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.1143G>A	p.Lys381Lys	synonymous	Exon 1 of 1	ENSP00000345708.4	Q14654-1
	KCNJ11	ENST00000528731.1	TSL:1	c.882G>A	p.Lys294Lys	synonymous	Exon 2 of 2	ENSP00000434755.1	Q14654-2
	KCNJ11	ENST00000948565.1		c.1143G>A	p.Lys381Lys	synonymous	Exon 2 of 2	ENSP00000618624.1

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

GnomAD2 exomes AF: 0.0126 AC: 3147 AN: 250258 AF XY: 0.0126

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 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

African (AFR) AF: 0.00374 AC: 125 AN: 33466

American (AMR) AF: 0.00871 AC: 389 AN: 44652

Ashkenazi Jewish (ASJ) AF: 0.0210 AC: 547 AN: 26044

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39690

South Asian (SAS) AF: 0.00538 AC: 463 AN: 86124

European-Finnish (FIN) AF: 0.00546 AC: 291 AN: 53262

Middle Eastern (MID) AF: 0.0201 AC: 116 AN: 5762

European-Non Finnish (NFE) AF: 0.0218 AC: 24281 AN: 1111526

Other (OTH) AF: 0.0170 AC: 1026 AN: 60348

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

African (AFR) AF: 0.00430 AC: 179 AN: 41584

American (AMR) AF: 0.0101 AC: 155 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0207 AC: 72 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5164

South Asian (SAS) AF: 0.00518 AC: 25 AN: 4830

European-Finnish (FIN) AF: 0.00292 AC: 31 AN: 10628

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0210 AC: 1429 AN: 68004

Other (OTH) AF: 0.0184 AC: 39 AN: 2114

Alfa AF: 0.0182 Hom.: 54

Bravo AF: 0.0129

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.0230

EpiControl AF: 0.0202

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	1	2	Hyperinsulinemic hypoglycemia, familial, 2 (3)
-	-	3	not provided (3)
-	-	1	Diabetes mellitus, transient neonatal, 3 (1)
-	1	-	Hyperinsulinemia (1)
-	-	1	Maturity-onset diabetes of the young type 13 (1)
-	-	1	Permanent neonatal diabetes mellitus (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	8.8
DANN	Benign	0.90
PhyloP100		0.82
Mutation Taster		=100/0	polymorphism (auto)

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: rs8175351; hg19: chr11-17408496;