rs80356669

Positions:

chr11-2159920-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000207.3(INS):c.265C>T(p.Arg89Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R89L) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

INS
NM_000207.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6U:1O:2

Conservation

PhyloP100: 0.612

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:):

INS-IGF2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000207.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-2159919-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13380.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.975

PP5

Variant 11-2159920-G-A is Pathogenic according to our data. Variant chr11-2159920-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 21117.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2159920-G-A is described in Lovd as [Pathogenic]. Variant chr11-2159920-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INS	NM_000207.3 linkuse as main transcript	c.265C>T	p.Arg89Cys	missense_variant	3/3	ENST00000381330.5
INS-IGF2	NR_003512.4 linkuse as main transcript	n.246+865C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INS	ENST00000381330.5 linkuse as main transcript	c.265C>T	p.Arg89Cys	missense_variant	3/3	1	NM_000207.3	P1	P01308-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1450698

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

720482

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.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6Uncertain:1Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Permanent neonatal diabetes mellitus

Pathogenic:1Other:2

not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 04, 2015	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 17, 2023	This missense change has been observed in individual(s) with autosomal dominant neonatal diabetes (PMID: 17855560, 22957706). 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. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 89 of the INS protein (p.Arg89Cys). ClinVar contains an entry for this variant (Variation ID: 21117). For these reasons, this variant has been classified as Pathogenic. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2023	Published in vitro functional studies suggest a negative effect on subcellular insulin localization and incomplete processing of proinsulin to insulin, but no inhibition of wildtype insulin secretion (Rajan et al., 2010); Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 28597946, 23074673, 23771172, 18162506, 20034470, 22957706, 17855560, 19900242, 28667717, 23050777, 25555642, 18171712, 28323911, 31605659, 35518939, 34593315, 32792356, 19952343) -

Diabetes mellitus, permanent neonatal 4

Pathogenic:1Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2008	- -
Uncertain significance, flagged submission	research	Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	-	Potent mutations in INS gene can cause early onset diabetes mellitus which is insulin dependent. May have poor response to sulfonylureas, as potent mutations in this gene can cause beta cell destruction.However, more evidence is required to confer the association of this particular variant R89C/ rs80356669 with Permanent neonatal diabetes mellitus(PNDM) -

Neonatal diabetes mellitus

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Molecular Genetics, Madras Diabetes Research Foundation

- -

INS-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 10, 2024

The INS c.265C>T variant is predicted to result in the amino acid substitution p.Arg89Cys. This variant, also known as p.Arg65Cys using legacy nomenclature, has been reported in several individuals, often occurring de novo, with permanent neonatal diabetes (Støy et al. 2007. PubMed ID: 17855560; Moritani et al. 2012. PubMed ID: 22957706; Fu et al. 2019. PubMed ID: 31605659; Lin Y et al 2020. PubMed ID: 32792356; Globa et al. 2022. PubMed ID: 36398453). In vitro studies demonstrate that expression of this variant results in aberrant processing of proinsulin to insulin and retainment in the endoplasmic reticulum (Rajan et al. 2009. PubMed ID: 19952343; Park et al. 2009. PubMed ID: 20034470). This variant has not been reported in a large population database, indicating this variant is rare. Additionally, different missense changes impacting the same amino acid (p.Arg89Pro, p.Arg89His, and p.Arg89Leu) have also been reported in association with hyperproinsulinemia and diabetes (Robbins et al. 1984. PubMed ID: 6368587; Billings et al. 2022. PubMed ID: 36208030). Taken together, the c.265C>T (p.Arg89Cys) variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

D;D;D;.

Eigen

Uncertain

0.35

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.95

.;.;D;D

M_CAP

Pathogenic

0.80

MetaRNN

Pathogenic

0.98

D;D;D;D

MetaSVM

Pathogenic

0.87

MutationAssessor

Pathogenic

3.8

H;H;H;.

MutationTaster

Benign

1.0

A;A;A;A;A;A

PROVEAN

Pathogenic

-4.4

D;D;D;D

REVEL

Pathogenic

0.82

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Uncertain

0.0020

D;D;D;D

Polyphen

1.0

D;D;D;D

Vest4

0.85

MutPred

0.81

Gain of methylation at K88 (P = 0.0249);Gain of methylation at K88 (P = 0.0249);Gain of methylation at K88 (P = 0.0249);.;

MVP

0.99

MPC

1.3

ClinPred

0.99

GERP RS

2.7

Varity_R

0.89

gMVP

0.97

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

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