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), Genomics England PanelApp, G2P
• monogenic diabetes

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

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNJ11	NM_000525.4	c.*215C>T		3_prime_UTR_variant	Exon 1 of 1	ENST00000339994.5	NP_000516.3
KCNJ11	NM_001166290.2	c.*215C>T		3_prime_UTR_variant	Exon 2 of 2		NP_001159762.1
KCNJ11	NM_001377296.1	c.*215C>T		3_prime_UTR_variant	Exon 3 of 3		NP_001364225.1
KCNJ11	NM_001377297.1	c.*215C>T		3_prime_UTR_variant	Exon 2 of 2		NP_001364226.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNJ11	ENST00000339994.5	c.*215C>T		3_prime_UTR_variant	Exon 1 of 1	6	NM_000525.4	ENSP00000345708.4

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

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Oct 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Type 2 diabetes mellitus Benign:1

-

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

Mutations in KCNJ11 gene can cause decreased production and secretion of insulin. This can lead to MODY which is responsive to oral sulfonylureas. rs5210 variant of KCNJ11 is associated with increased T2D risk. -

Diabetes mellitus, transient neonatal, 3 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Hyperinsulinemic hypoglycemia, familial, 2 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Maturity-onset diabetes of the young type 13 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs5210; hg19: chr11-17408251;