chr11-2161302-G-T

Variant names:

• chr11-2161302-G-T
• rs748749585

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP4

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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: -2.01

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 rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152022 Hom.: 0 Cov.: 33

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: 17 AN: 161264 Hom.: 0 Cov.: 0 AF XY: 0.000123 AC XY: 10 AN XY: 81586

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: 25 AN: 152022 Hom.: 0 Cov.: 33 AF XY: 0.000189 AC XY: 14 AN XY: 74252

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:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Apr 05, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Jul 22, 2020

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the INS gene demonstrated a heterozygous sequence change in the 5’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). -

Permanent neonatal diabetes mellitus Pathogenic:1 Other:1

Jan 17, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: INS c.-152C>A, also known as c.-331C>A, is located in the untranscribed region upstream of the INS gene region. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00013 in 313286 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in INS causing Neonatal Diabetes Mellitus, allowing no conclusion about variant significance. c.-152C>A has been reported in the literature in multiple homozygous individuals affected with recessive Neonatal Diabetes Mellitus (Garin_2010, Flanagan_2014, Nayak_2021, Demiral_2020, Demirbilek_2015). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a significant reduction in promoter activity (Garin_2010). The following publications have been ascertained in the context of this evaluation (PMID: 32656923, 25755231, 24411943, 20133622, 33409956). ClinVar contains an entry for this variant (Variation ID: 431442). To our knowledge, this variant has not been reported in individuals with dominant Neonatal Diabetes Mellitus. Based on the evidence outlined above, this variant is pathogenic for recessive Neonatal Diabetes Mellitus. -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Hyperproinsulinemia;C1852092:Type 1 diabetes mellitus 2;C3150617:Maturity-onset diabetes of the young type 10;C5394307:Diabetes mellitus, permanent neonatal 4 Pathogenic:1

Mar 19, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

INS-related disorder Pathogenic:1

Feb 27, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

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

Other links and lift over

dbSNP: rs748749585; hg19: chr11-2182532;