chr11-2160028-C-T

Position:

• chr11-2160028-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The ENST00000381330.5(INS):​c.188-31G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely risk allele (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: INS ENST00000381330.5 intron
• Clinical Significance: Pathogenic/Likely risk allele criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 0.540

Genes affected

INS (HGNC:6081): (insulin) This gene encodes insulin, a peptide hormone that plays a vital role in the regulation of carbohydrate and lipid metabolism. After removal of the precursor signal peptide, proinsulin is post-translationally cleaved into three peptides: the B chain and A chain peptides, which are covalently linked via two disulfide bonds to form insulin, and C-peptide. Binding of insulin to the insulin receptor (INSR) stimulates glucose uptake. A multitude of mutant alleles with phenotypic effects have been identified, including insulin-dependent diabetes mellitus, permanent neonatal diabetes diabetes mellitus, maturity-onset diabetes of the young type 10 and hyperproinsulinemia. There is a read-through gene, INS-IGF2, which overlaps with this gene at the 5' region and with the IGF2 gene at the 3' region. [provided by RefSeq, May 2020]

INS-IGF2 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-2160028-C-T is Pathogenic according to our data. Variant chr11-2160028-C-T is described in ClinVar as [Likely_risk_allele]. Clinvar id is 211186.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_risk_allele=2, Pathogenic=7}. Variant chr11-2160028-C-T is described in Lovd as [Likely_pathogenic]. Variant chr11-2160028-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INS	NM_000207.3	c.188-31G>A		intron_variant		ENST00000381330.5	NP_000198.1
INS-IGF2	NR_003512.4	n.246+757G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INS	ENST00000381330.5	c.188-31G>A		intron_variant		1	NM_000207.3	ENSP00000370731	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1406148 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 695738

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely risk allele

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 12, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 28, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 25, 2021	Published functional studies demonstrate a damaging effect; variant leads to the inclusion of 29 base pairs and an altered reading frame (Garin et al., 2012); In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing; This variant is associated with the following publications: (PMID: 25721872, 24622368, 25306193, 30414308, 22235272) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 27, 2023	This variant has been observed in individual(s) with maturity onset diabetes of the young and/or permanent neonatal diabetes mellitus (PMID: 22235272, 24622368, 25721872, 30414308). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 211186). Studies have shown that this variant results in activation of a cryptic splice site and introduces a new termination codon (PMID: 22235272). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 2 of the INS gene. It does not directly change the encoded amino acid sequence of the INS protein. RNA analysis indicates that this variant induces altered splicing and likely disrupts the C-terminus of the protein. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 19, 2023	The INS c.188-31G>A variant (rs797045623) is reported in the literature in multiple individuals and families affected with maturity onset diabetes of the young or permanent neonatal diabetes mellitus (Alkorta-Aranburu 2014, Busiah 2013, Dusatkova 2015, Garin 2012, Matsuno 2019). This variant is also reported in ClinVar (Variation ID: 211186), and is absent from the Genome Aggregation Database, but is considered a low confidence variant in the database. This is an intronic variant, and computational analyses (Alamut Visual Plus v.1.5.1) predict that this variant may impact splicing by creating a novel cryptic acceptor splice site and weakening the nearby canonical acceptor splice site. Additionally, functional studies demonstrate inclusion of 29 nucleotides of intron 2, and while this may not lead to nonsense-mediated decay, it is expected to create a truncated protein with an altered C-terminus (Garin 2012). Based on available information, this variant is considered to be pathogenic. References: Alkorta-Aranburu G et al. Phenotypic heterogeneity in monogenic diabetes: the clinical and diagnostic utility of a gene panel-based next-generation sequencing approach. Mol Genet Metab. 2014 Dec;113(4):315-320. PMID: 25306193. Busiah K et al. Neuropsychological dysfunction and developmental defects associated with genetic changes in infants with neonatal diabetes mellitus: a prospective cohort study (corrected). Lancet Diabetes Endocrinol. 2013 Nov;1(3):199-207. PMID: 24622368. Dusatkova L et al. Frameshift mutations in the insulin gene leading to prolonged molecule of insulin in two families with Maturity-Onset Diabetes of the Young. Eur J Med Genet. 2015 Apr;58(4):230-4. PMID: 25721872. Garin I et al. Permanent neonatal diabetes caused by creation of an ectopic splice site within the INS gene. PLoS One. 2012;7(1):e29205. PMID: 22235272. Matsuno S et al. Identification of a variant associated with early-onset diabetes in the intron of the insulin gene with exome sequencing. J Diabetes Investig. 2019 Jul;10(4):947-950. PMID: 30414308. -

Permanent neonatal diabetes mellitus Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 30, 2015	- -

Neonatal insulin-dependent diabetes mellitus Pathogenic:1

Likely risk allele, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

-

Mutations in INS gene can cause early onset diabetes mellitus which is insulin dependent. May have poor response to sulfonylureas, as this mutation can cause beta cell destruction. However no sufficient evidence is found to ascertain the role of this particular variant rs797045623, yet. -

Diabetes mellitus, permanent neonatal 4 Pathogenic:1

Likely risk allele, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

-

Potent mutations in the INS gene can cause early onset diabetes mellitus which is insulin dependent. May have poor response to sulfonylureas, mutations in this gene can cause beta cell destruction.Sufficient evidence is found to confer the association of this particular variant c.188-31G>A/rs797045623 with neonatal diabetes. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	17
DANN	Benign	0.38
BranchPoint Hunter		3.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.98		Position offset: -2
DS_AL_spliceai		0.75		Position offset: -31

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

Publications

LitVar

Other links and lift over

dbSNP: rs797045623; hg19: chr11-2181258;