rs121908259

chr11-2160955-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 4P and 6B. PM1 PM5 BP4_Moderate BS2

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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R6C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 35)
  • Exomes 𝑓: 0.000090 (0 hom.)
• Consequence: INS NM_000207.3 missense
• Clinical Significance: Uncertain significance/Uncertain risk allele criteria provided, multiple submitters, no conflicts U:2 O:2
• Conservation: PhyloP100: 0.142

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 Likely_benign. Variant got -2 ACMG points.

• PM1: In a signal_peptide (size 23) in uniprot entity INS_HUMAN there are 7 pathogenic changes around while only 2 benign (78%) in NM_000207.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-2160956-G-A is described in ClinVar as [Likely_risk_allele]. Clinvar id is 13390.Status of the report is criteria_provided_single_submitter, 1 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_risk_allele=1, not_provided=1}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.17572835).
• BS2: High AC in GnomAd at 28 AD gene.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INS	ENST00000381330.5	c.17G>A	p.Arg6His	missense_variant	2/3	1	NM_000207.3	P1

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152184 Hom.: 0 Cov.: 35

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: 23 AN: 246470 Hom.: 0 AF XY: 0.0000895 AC XY: 12 AN XY: 134134

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.: 0 Cov.: 88 AF XY: 0.0000977 AC XY: 71 AN XY: 726374

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: 28 AN: 152184 Hom.: 0 Cov.: 35 AF XY: 0.000148 AC XY: 11 AN XY: 74350

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.: 0

Bravo AF: 0.000204

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000661 AC: 8

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance/Uncertain risk allele

Submissions summary: Uncertain:2 Other:2

Revision: criteria provided, multiple submitters, no conflicts

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

Invitae

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	T
BayesDel_noAF	Pathogenic	0.14
Cadd	Benign	17
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	N
LIST_S2	Benign	0.75	T;.;.;T;T;T
M_CAP	Pathogenic	0.37	D
MetaRNN	Benign	0.18	T;T;T;T;T;T
MetaSVM	Uncertain	0.012	D
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	T
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

Other links and lift over

dbSNP: rs121908259; hg19: chr11-2182185;