chr11-2159919-C-T

Position:

chr11-2159919-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 16P and 1B. PM1PM5PP3_StrongPP5_Very_StrongBS2_Supporting

The ENST00000381330.5(INS):c.266G>A(p.Arg89His) variant causes a missense change. The variant allele was found at a frequency of 0.00000748 in 1,603,692 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. R89L) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

INS
ENST00000381330.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4U:1

Conservation

PhyloP100: 5.33

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 15 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 ENST00000381330.5

PM5

Other missense variant is known to change same aminoacid residue: 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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.975

PP5

Variant 11-2159919-C-T is Pathogenic according to our data. 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.

BS2

High AC in GnomAdExome4 at 9 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INS	NM_000207.3 linkuse as main transcript	c.266G>A	p.Arg89His	missense_variant	3/3	ENST00000381330.5	NP_000198.1
INS-IGF2	NR_003512.4 linkuse as main transcript	n.246+866G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INS	ENST00000381330.5 linkuse as main transcript	c.266G>A	p.Arg89His	missense_variant	3/3	1	NM_000207.3	ENSP00000370731	P1	P01308-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000435

AC:

AN:

229810

Hom.:

AF XY:

0.00000805

AC XY:

AN XY:

124174

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000966

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000620

AC:

AN:

1451498

Hom.:

Cov.:

AF XY:

0.00000694

AC XY:

AN XY:

720976

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:

0.00000722

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.00000830

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hyperproinsulinemia

Pathogenic:2Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 1998	- -
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 rs28933985 (Arg65His) with hyperproinsulinemia. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 03, 2022	Variant summary: INS c.266G>A (p.Arg89His) results in a non-conservative amino acid change located in the Insulin-like domain (IPR016179) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-06 in 229810 control chromosomes (gnomAD). p.Arg89His (also described in the literature as Arg65His) has been reported in multiple individuals/families affected with Hyperproinsulinemia (e.g. Shibasaki_1995, Barbetti_1990, Oohashi_1993, Roder_1996, Collinet_1998). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed the variant protein was properly sorted to secretory granules and efficiently secreted (Park_2010). A ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic for Hyperproinsulinemia. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2020

- -

INS-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 14, 2022

The INS c.266G>A variant is predicted to result in the amino acid substitution p.Arg89His. This variant, also known as p.Arg65His using legacy nomenclature, has been reported in multiple individuals with hyperproinsulinemia (Robbins DC et al 1984. PubMed ID: 6368587; Shibasaki et al 1985. PubMed ID: 4019786; Röder ME et al 1996. PubMed ID: 8636380; Collinet M et al 1998. PubMed ID: 9667398; Park et al. 2010. PubMed ID: 20034470). This variant is reported in 0.00097% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-2181149-C-T). Alternative variants at the same amino acid ( p.Arg89Cys, p.Arg89Pro, and p.Arg89Leu) have also been reported in association with hyperproinsulinemia and diabetes (Human Gene Mutation Database; http://www.hgmd.cf.ac.uk/). This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.39

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

D;D;D;.

Eigen

Uncertain

0.34

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.93

.;.;D;D

M_CAP

Pathogenic

0.71

MetaRNN

Pathogenic

0.97

D;D;D;D

MetaSVM

Uncertain

0.77

MutationAssessor

Pathogenic

3.8

H;H;H;.

MutationTaster

Benign

1.0

D;D;D;D;D;D

PROVEAN

Uncertain

-2.7

D;D;D;D

REVEL

Pathogenic

0.79

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Uncertain

0.0050

D;D;D;D

Polyphen

1.0

D;D;D;D

Vest4

0.81

MutPred

0.85

Gain of catalytic residue at G90 (P = 0.0436);Gain of catalytic residue at G90 (P = 0.0436);Gain of catalytic residue at G90 (P = 0.0436);.;

MVP

0.97

MPC

1.3

ClinPred

0.97

GERP RS

2.7

Varity_R

0.91

gMVP

0.94

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