11-2160878-C-T

Variant names:

Variant summary

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

The NM_000207.3(INS):c.94G>A(p.Gly32Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,384 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. G32R) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 35)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

INS
NM_000207.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7U:1O:3

Conservation

PhyloP100: 5.58

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a peptide Insulin B chain (size 29) in uniprot entity INS_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) 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 chr11-2160878-C-G is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.94

PP5

Variant 11-2160878-C-T is Pathogenic according to our data. Variant chr11-2160878-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 21122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2160878-C-T is described in Lovd as [Pathogenic]. Variant chr11-2160878-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INS	NM_000207.3 link	c.94G>A	p.Gly32Ser	missense_variant	Exon 2 of 3	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.94G>A	p.Gly32Ser	missense_variant	Exon 2 of 3	1	NM_000207.3	ENSP00000370731.5		P01308-1
INS-IGF2	ENST00000397270.1 link	c.94G>A	p.Gly32Ser	missense_variant	Exon 2 of 5	1		ENSP00000380440.1		F8WCM5-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460384

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726528

show subpopulations

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7Uncertain:1Other:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Diabetes mellitus, permanent neonatal 4

Pathogenic:2Uncertain:1

Sep 18, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Uncertain significance

Review Status: flagged submission

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 G32S/rs80356664 with Neonatal diabetes. -

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PS4_Moderate+PS2+PP4+PP3_Strong -

Permanent neonatal diabetes mellitus

Pathogenic:1Other:2

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jul 21, 2021

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Gly32Ser variant in INS has been reported in at least 15 individuals with early-onset or infantile diabetes, including 8 de novo occurrences, and segregated with disease in 4 affected individuals from 1 family (Stoy 2007 PMID:17855560, Edghill 2008 PMID: 18162506, Bonfanti 2009 PMID: 18840770, Rubio-Cabezas 2009 PMID: 19900242, Jahnavi 2013 PMID: 22831748, Globa 2015 PMID: 26208381, Ortolani 2015 PMID: 26239141, Brahm 2016 PMID: 27634015, Wasserman 2016 PMID: 26530398, Urrutia 2019 PMID: 31365591, Fu 2020 PMID: 31605659, Lin 2020 PMID: 32792356). It was absent from large population studies but has been reported in ClinVar (Variation ID 21122). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies support an impact on protein function (Park 2010 PMID: 20034470, Rajan 2010 PMID: 19952343). Animal models in mice support that this variant causes diabetes (Austin 2020 PMID: 32994272). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant monogenic diabetes. ACMG/AMP Criteria applied: PS4, PM6_Strong, PM2_Supporting, PS3_Moderate, PP1, PP3. -

not provided

Pathogenic:2

Jun 27, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies suggest a damaging effect on protein function (PMID: 20034470); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17855560, 18162506, 19900242, 27634015, 31365591, 31605659, 18840770, 19952343, 26530398, 31264968, 32792356, 32041611, 37897565, 37048081, 36398453, 36151994, 36504295, 36724370, 36418577, 34387403, 38793013, 36655002, 35518939, 20034470) -

Dec 30, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 32 of the INS protein (p.Gly32Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant permanent neonatal diabetes mellitus (PMID: 17855560). 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: 21122). 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. Experimental studies have shown that this missense change affects INS function (PMID: 19952343). For these reasons, this variant has been classified as Pathogenic. -

Neonatal diabetes mellitus

Pathogenic:1Other:1

Apr 03, 2015

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

Significance: not provided

Review Status: no classification provided

Collection Method: clinical testing

- -

Molecular Genetics, Madras Diabetes Research Foundation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Type 1 diabetes mellitus 2

Pathogenic:1

Nov 04, 2013

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.82

D;D;D;D;.;.

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.97

D;.;.;D;D;D

M_CAP

Pathogenic

0.93

MetaRNN

Pathogenic

0.94

D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

0.69

N;.;.;.;.;.

PROVEAN

Pathogenic

-5.7

D;D;D;D;D;D

REVEL

Pathogenic

0.96

Sift

Uncertain

0.0040

D;D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;.;D

Polyphen

1.0

D;D;D;D;.;D

Vest4

0.87

MVP

0.84

MPC

0.90

ClinPred

1.0

GERP RS

3.9

Varity_R

0.98

gMVP

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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