rs5210

Variant names:

• chr11-17386704-G-A
• rs5210
• NM_000525.4:c.*215C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-17386704-G-A
• chr11-17386704-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000525.4(KCNJ11):​c.*215C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.394 in 568,352 control chromosomes in the GnomAD database, including 46,171 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (15056 hom., cov: 33)
  • Exomes 𝑓: 0.38 (31115 hom.)
• Consequence: KCNJ11 NM_000525.4 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.608
• Publications: 54 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 11-17386704-G-A is Benign according to our data. Variant chr11-17386704-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 303727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.564 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.*215C>T		3_prime_UTR	Exon 1 of 1	NP_000516.3
	KCNJ11	NM_001166290.2		c.*215C>T		3_prime_UTR	Exon 2 of 2	NP_001159762.1	A0A804HHV7
	KCNJ11	NM_001377296.1		c.*215C>T		3_prime_UTR	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.*215C>T		3_prime_UTR	Exon 1 of 1	ENSP00000345708.4	Q14654-1
	KCNJ11	ENST00000528731.1	TSL:1	c.*215C>T		3_prime_UTR	Exon 2 of 2	ENSP00000434755.1	Q14654-2
	KCNJ11	ENST00000948565.1		c.*215C>T		3_prime_UTR	Exon 2 of 2	ENSP00000618624.1

Frequencies

GnomAD3 genomes AF: 0.433 AC: 65822 AN: 151918 Hom.: 15020 Cov.: 33

Gnomad AFR AF: 0.570

Gnomad AMI AF: 0.302

Gnomad AMR AF: 0.391

Gnomad ASJ AF: 0.300

Gnomad EAS AF: 0.559

Gnomad SAS AF: 0.359

Gnomad FIN AF: 0.367

Gnomad MID AF: 0.386

Gnomad NFE AF: 0.376

Gnomad OTH AF: 0.399

GnomAD4 exome AF: 0.379 AC: 157914 AN: 416316 Hom.: 31115 Cov.: 3 AF XY: 0.376 AC XY: 81769 AN XY: 217688

African (AFR) AF: 0.566 AC: 6739 AN: 11900

American (AMR) AF: 0.358 AC: 5949 AN: 16632

Ashkenazi Jewish (ASJ) AF: 0.288 AC: 3752 AN: 13014

East Asian (EAS) AF: 0.524 AC: 15428 AN: 29432

South Asian (SAS) AF: 0.339 AC: 13305 AN: 39298

European-Finnish (FIN) AF: 0.355 AC: 9849 AN: 27728

Middle Eastern (MID) AF: 0.333 AC: 615 AN: 1846

European-Non Finnish (NFE) AF: 0.368 AC: 92851 AN: 252096

Other (OTH) AF: 0.387 AC: 9426 AN: 24370

GnomAD4 genome AF: 0.434 AC: 65921 AN: 152036 Hom.: 15056 Cov.: 33 AF XY: 0.436 AC XY: 32379 AN XY: 74318

African (AFR) AF: 0.570 AC: 23661 AN: 41492

American (AMR) AF: 0.391 AC: 5975 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.300 AC: 1039 AN: 3468

East Asian (EAS) AF: 0.560 AC: 2880 AN: 5142

South Asian (SAS) AF: 0.359 AC: 1729 AN: 4818

European-Finnish (FIN) AF: 0.367 AC: 3885 AN: 10586

Middle Eastern (MID) AF: 0.391 AC: 115 AN: 294

European-Non Finnish (NFE) AF: 0.376 AC: 25512 AN: 67930

Other (OTH) AF: 0.402 AC: 851 AN: 2116

Alfa AF: 0.291 Hom.: 882

Bravo AF: 0.436

Asia WGS AF: 0.485 AC: 1688 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	13
DANN	Benign	0.70
PhyloP100		0.61
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

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

Other links and lift over

dbSNP: rs5210;

hg19: chr11-17408251;