rs5210

Positions:

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

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id 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/exons	MANE	Protein	UniProt
KCNJ11	NM_000525.4	c.*215C>T		3_prime_UTR_variant	1/1	ENST00000339994.5	NP_000516.3
KCNJ11	NM_001166290.2	c.*215C>T		3_prime_UTR_variant	2/2		NP_001159762.1
KCNJ11	NM_001377296.1	c.*215C>T		3_prime_UTR_variant	3/3		NP_001364225.1
KCNJ11	NM_001377297.1	c.*215C>T		3_prime_UTR_variant	2/2		NP_001364226.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNJ11	ENST00000339994.5	c.*215C>T		3_prime_UTR_variant	1/1		NM_000525.4	ENSP00000345708	P1

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

Gnomad4 AFR exome AF: 0.566

Gnomad4 AMR exome AF: 0.358

Gnomad4 ASJ exome AF: 0.288

Gnomad4 EAS exome AF: 0.524

Gnomad4 SAS exome AF: 0.339

Gnomad4 FIN exome AF: 0.355

Gnomad4 NFE exome AF: 0.368

Gnomad4 OTH exome AF: 0.387

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

Gnomad4 AFR AF: 0.570

Gnomad4 AMR AF: 0.391

Gnomad4 ASJ AF: 0.300

Gnomad4 EAS AF: 0.560

Gnomad4 SAS AF: 0.359

Gnomad4 FIN AF: 0.367

Gnomad4 NFE AF: 0.376

Gnomad4 OTH AF: 0.402

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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Type 2 diabetes mellitus Benign:1

Benign, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

-

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

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs5210; hg19: chr11-17408251;