11-2160955-C-T

Position:

chr11-2160955-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_000207.3(INS):c.17G>A(p.Arg6His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000986 in 1,612,270 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 Uncertain risk allele (★★).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 35)

Exomes 𝑓: 0.000090 ( 0 hom. )

Consequence

INS
NM_000207.3 missense

Scores

Clinical Significance

Uncertain significance/Uncertain risk allele criteria provided, multiple submitters, no conflicts U:2O:2

Conservation

PhyloP100: 0.142

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 Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.17572835).

BS2

High AC in GnomAd4 at 28 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INS	NM_000207.3 linkuse as main transcript	c.17G>A	p.Arg6His	missense_variant	2/3	ENST00000381330.5	NP_000198.1
INS-IGF2	NR_003512.4 linkuse as main transcript	n.76G>A		non_coding_transcript_exon_variant	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INS	ENST00000381330.5 linkuse as main transcript	c.17G>A	p.Arg6His	missense_variant	2/3	1	NM_000207.3	ENSP00000370731	P1	P01308-1

Frequencies

GnomAD3 genomes

AF:

0.000184

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000507

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000933

AC:

AN:

246470

Hom.:

AF XY:

0.0000895

AC XY:

AN XY:

134134

show subpopulations

Gnomad AFR exome

AF:

0.000438

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000912

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000897

AC:

131

AN:

1460086

Hom.:

Cov.:

AF XY:

0.0000977

AC XY:

AN XY:

726374

show subpopulations

Gnomad4 AFR exome

AF:

0.000657

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.000139

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000792

Gnomad4 OTH exome

AF:

0.0000829

GnomAD4 genome

AF:

0.000184

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.000507

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000135

Hom.:

Bravo

AF:

0.000204

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000661

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance/Uncertain risk allele

Submissions summary: Uncertain:2Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Maturity-onset diabetes of the young type 10

Other:2

not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -
Uncertain 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 R6H/rs121908259 with Maturity-onset diabetes of the young (MODY). -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 05, 2024

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 6 of the INS protein (p.Arg6His). This variant is present in population databases (rs121908259, gnomAD 0.03%). This missense change has been observed in individual(s) with autosomal dominant maturity onset diabetes of the young (MODY) or type 2 diabetes (PMID: 20007936, 24097065, 29758564). ClinVar contains an entry for this variant (Variation ID: 68727). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Not Available"; Align-GVGD: "Not Available". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects INS function (PMID: 20007936, 24770419). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

INS-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 12, 2023

The INS c.17G>A variant is predicted to result in the amino acid substitution p.Arg6His. This variant has been reported in individuals with Maturity Onset Diabetes of the Young (MODY) (Meur et al 2010. PubMed ID: 20007936; de Santana et al. 2019. PubMed ID: 31595705). In vitro function studies indicate that this variant leads to impaired preproinsulin translocation across the endoplasmic reticulum membrane and accumulation of untranslocated preproinsulin in cytosol (Guo H et al 2014. PubMed ID: 24770419). However, another study showed that secretion of this mutant protein was not significantly different from wild type (Meur et al 2010. PubMed ID: 20007936). This variant is reported in 0.032% of alleles i n individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-2182185-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Uncertain

0.031

BayesDel_noAF

Pathogenic

0.14

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.017

T;T;T;T;.;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.016

LIST_S2

Benign

0.75

T;.;.;T;T;T

M_CAP

Pathogenic

0.37

MetaRNN

Benign

0.18

T;T;T;T;T;T

MetaSVM

Uncertain

0.012

MutationAssessor

Benign

0.55

N;.;.;.;.;.

MutationTaster

Benign

1.0

N;N;N;N;N;N

PROVEAN

Benign

-0.58

N;N;N;N;N;N

REVEL

Uncertain

0.59

Sift

Benign

0.052

T;T;T;T;T;T

Sift4G

Benign

0.14

T;T;T;T;.;T

Polyphen

0.022

B;B;B;B;.;B

Vest4

0.21

MVP

0.17

MPC

0.32

ClinPred

0.027

GERP RS

0.62

Varity_R

0.037

gMVP

0.65

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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