11-17388597-CAA-CA

Variant names:

• chr11-17388597-CA-C
• rs35513985
• NM_000525.4:c.-507delT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000525.4(KCNJ11):​c.-507delT variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (14886 hom., cov: 0)
  • Exomes 𝑓: 0.35 (10806 hom.)
• Consequence: KCNJ11 NM_000525.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.209
• Publications: 1 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: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• monogenic diabetes

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

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Myriad Women's Health, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P
• 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 -16 ACMG points.

• BP6: Variant 11-17388597-CA-C is Benign according to our data. Variant chr11-17388597-CA-C is described in ClinVar as Benign. ClinVar VariationId is 435554.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.56 is higher than 0.05.

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.-507delT		5_prime_UTR	Exon 1 of 1	NP_000516.3
	KCNJ11	NM_001166290.2		c.-17+576delT		intron	N/A	NP_001159762.1	A0A804HHV7
	KCNJ11	NM_001377296.1		c.-76+243delT		intron	N/A	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.-507delT		5_prime_UTR	Exon 1 of 1	ENSP00000345708.4	Q14654-1
	KCNJ11	ENST00000528731.1	TSL:1	c.-17+576delT		intron	N/A	ENSP00000434755.1	Q14654-2
	KCNJ11	ENST00000948565.1		c.-255+243delT		intron	N/A	ENSP00000618624.1

Frequencies

GnomAD3 genomes AF: 0.432 AC: 65355 AN: 151244 Hom.: 14853 Cov.: 0

Gnomad AFR AF: 0.566

Gnomad AMI AF: 0.303

Gnomad AMR AF: 0.390

Gnomad ASJ AF: 0.300

Gnomad EAS AF: 0.560

Gnomad SAS AF: 0.358

Gnomad FIN AF: 0.366

Gnomad MID AF: 0.382

Gnomad NFE AF: 0.376

Gnomad OTH AF: 0.398

GnomAD4 exome AF: 0.355 AC: 55060 AN: 155236 Hom.: 10806 Cov.: 0 AF XY: 0.351 AC XY: 30016 AN XY: 85410

African (AFR) AF: 0.539 AC: 1614 AN: 2996

American (AMR) AF: 0.340 AC: 2534 AN: 7448

Ashkenazi Jewish (ASJ) AF: 0.274 AC: 841 AN: 3072

East Asian (EAS) AF: 0.502 AC: 2018 AN: 4016

South Asian (SAS) AF: 0.336 AC: 10987 AN: 32724

European-Finnish (FIN) AF: 0.342 AC: 6469 AN: 18898

Middle Eastern (MID) AF: 0.340 AC: 250 AN: 736

European-Non Finnish (NFE) AF: 0.355 AC: 27873 AN: 78522

Other (OTH) AF: 0.363 AC: 2474 AN: 6824

GnomAD4 genome AF: 0.432 AC: 65451 AN: 151364 Hom.: 14886 Cov.: 0 AF XY: 0.434 AC XY: 32107 AN XY: 73932

African (AFR) AF: 0.566 AC: 23346 AN: 41238

American (AMR) AF: 0.390 AC: 5944 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.300 AC: 1038 AN: 3462

East Asian (EAS) AF: 0.561 AC: 2834 AN: 5056

South Asian (SAS) AF: 0.359 AC: 1723 AN: 4804

European-Finnish (FIN) AF: 0.366 AC: 3853 AN: 10522

Middle Eastern (MID) AF: 0.387 AC: 113 AN: 292

European-Non Finnish (NFE) AF: 0.376 AC: 25482 AN: 67748

Other (OTH) AF: 0.402 AC: 843 AN: 2098

Alfa AF: 0.247 Hom.: 524

Bravo AF: 0.434

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.21
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs35513985;

hg19: chr11-17410144;

COSMIC: COSV107400432;

COSMIC: COSV107400432;