Variant 11-2161302-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4

The variant allele was found at a frequency of 0.000134 in 313,286 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

Unknown

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3O:1

Conservation

PhyloP100: -2.01

Variant links:

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ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-2161302-G-T is Pathogenic according to our data. Variant chr11-2161302-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 431442.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt

Frequencies

GnomAD3 genomes

AF:

0.000164

AC:

AN:

152022

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000435

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000589

Gnomad OTH

AF:

0.000957

GnomAD4 exome

AF:

0.000105

AC:

AN:

161264

Hom.:

Cov.:

AF XY:

0.000123

AC XY:

AN XY:

81586

show subpopulations

Gnomad4 AFR exome

AF:

0.000160

Gnomad4 AMR exome

AF:

0.000140

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000764

Gnomad4 SAS exome

AF:

0.000200

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000111

Gnomad4 OTH exome

AF:

0.0000991

GnomAD4 genome

AF:

0.000164

AC:

AN:

152022

Hom.:

Cov.:

AF XY:

0.000189

AC XY:

AN XY:

74252

show subpopulations

Gnomad4 AFR

AF:

0.000435

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000589

Gnomad4 OTH

AF:

0.000957

Bravo

AF:

0.000212

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 05, 2023	Published functional studies demonstrate a damaging effect on INS promoter activity (Garin et al., 2010); Also referred to as c.-331C>A using alternate nomenclature; This variant is associated with the following publications: (PMID: 20301620, 20133622, 21592955, 20938745, 32656923, 34426871, 21808142, 33409956, 25755231) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 22, 2020	DNA sequence analysis of the INS gene demonstrated a heterozygous sequence change in the 5√¢‚Ç¨‚Ñ¢untranslated region, c.-152C>A. Garin et al., 2010, identified this sequence change (referred to as c.-331C>A) in the homozygous state in two unrelated individuals with transient neonatal diabetes (PMID 20133622). Interestingly, the carrier parents had normal glucose tolerance indicating that this single insulin allele is sufficient to provide the insulin required to maintain normal glycaemia. Functional studies demonstrated that this variant significantly impaired INS transcription in vitro (PMID 20133622). This sequence change is present at a low frequency of 0.0096% in the gnomAD population database (dbSNP rs748749585). -

INS-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 27, 2024

The INS c.-152C>A variant is located in the 5' untranslated region. This variant has been reported as a recessive, pathogenic allele for neonatal diabetes in two families due to insulin biosynthesis impairment (reported as c.-331C>A at Garin et al. 2010. PubMed ID: 20133622; Støy et al. 2010. PubMed ID: 20938745). Of note, heterozygous carrier parents in Garin et al. study were reported to be unaffected with neonatal diabetes. Moreover, another study showed that a different substitution at the same nucleotide position c.-152C>G occurs at a binding site of Kruppel-like transcription factor (KLF); this change causes a failure of binding Kruppel-like transcription factor 11 (KLF11) and hence inhibits KLF11-mediated INS activation (reported as c.-331C>G at Bonnefond et al. 2011. PubMed ID: 21592955). This variant is reported in 0.023% of alleles in individuals of African descent in gnomAD. This variant is interpreted as pathogenic. -

Permanent neonatal diabetes mellitus

Other:1

not provided, no classification provided

literature only

GeneReviews

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.64

DANN

Benign

0.86

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over