rs797045623

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_000207.3(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
NM_000207.3 intron

Scores

Clinical Significance

Pathogenic/Likely risk allele criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 0.540

Publications

10 publications found

Variant links:

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 links:

INS-IGF2 (HGNC:33527): (INS-IGF2 readthrough) This locus includes two alternatively spliced read-through transcript variants which align to the INS gene in the 5' region and to the IGF2 gene in the 3' region. One transcript is predicted to encode a protein which shares the N-terminus with the INS protein but has a distinct and longer C-terminus, whereas the other transcript is a candidate for nonsense-mediated decay (NMD). The transcripts are imprinted and are paternally expressed in the limb and eye. [provided by RefSeq, Jul 2008]

INS-IGF2 links:

ENSG00000295384 (HGNC:):

ENSG00000295384 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 11-2160028-C-T is Pathogenic according to our data. Variant chr11-2160028-C-T is described in ClinVar as Pathogenic/Likely_risk_allele. ClinVar VariationId is 211186.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INS	NM_000207.3 link	c.188-31G>A		intron_variant	Intron 2 of 2	ENST00000381330.5	NP_000198.1	P01308-1I3WAC9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INS	ENST00000381330.5 link	c.188-31G>A		intron_variant	Intron 2 of 2	1	NM_000207.3	ENSP00000370731.5		P01308-1
INS-IGF2	ENST00000397270.1 link	c.187+757G>A		intron_variant	Intron 2 of 4	1		ENSP00000380440.1		F8WCM5-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

167436

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1406148

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

695738

African (AFR)

AF:

0.00

AC:

AN:

32794

American (AMR)

AF:

0.00

AC:

AN:

37370

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25340

East Asian (EAS)

AF:

0.00

AC:

AN:

37640

South Asian (SAS)

AF:

0.00

AC:

AN:

80698

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39636

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4480

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1089622

Other (OTH)

AF:

0.00

AC:

AN:

58568

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000345

Hom.:

ClinVar

Significance: Pathogenic/Likely risk allele

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

May 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. This variant is not present in population databases (gnomAD no frequency). 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. -

Jun 28, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 25, 2021

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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) -

Oct 19, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jan 12, 2017

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Permanent neonatal diabetes mellitus

Pathogenic:2

May 28, 2019

Mendelics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 30, 2015

Genetic Services Laboratory, University of Chicago

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Neonatal insulin-dependent diabetes mellitus

Pathogenic:1

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance:Likely risk allele

Review Status:criteria provided, single submitter

Collection Method:research

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

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance:Likely risk allele

Review Status:criteria provided, single submitter

Collection Method:research

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

(source)

DANN

Benign

0.38

PhyloP100

0.54

BranchPoint Hunter

3.0

Mutation Taster

=5/95

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over