chr11-2159843-G-A

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000207.3(INS):c.*9C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.2 in 1,609,784 control chromosomes in the GnomAD database, including 34,089 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.17 ( 2322 hom., cov: 33)

Exomes 𝑓: 0.20 ( 31767 hom. )

Consequence

INS
NM_000207.3 3_prime_UTR

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8O:1

Conservation

PhyloP100: -5.12

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004797995).

BP6

Variant 11-2159843-G-A is Benign according to our data. Variant chr11-2159843-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 255531.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.215 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INS	NM_000207.3 link	c.*9C>T		3_prime_UTR_variant	Exon 3 of 3	ENST00000381330.5	NP_000198.1	P01308-1I3WAC9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INS	ENST00000381330 link	c.*9C>T		3_prime_UTR_variant	Exon 3 of 3	1	NM_000207.3	ENSP00000370731.5		P01308-1
INS-IGF2	ENST00000397270.1 link	c.187+942C>T		intron_variant	Intron 2 of 4	1		ENSP00000380440.1		F8WCM5-1

Frequencies

GnomAD3 genomes

AF:

0.166

AC:

25164

AN:

152042

Hom.:

2320

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0982

Gnomad AMI

AF:

0.316

Gnomad AMR

AF:

0.161

Gnomad ASJ

AF:

0.214

Gnomad EAS

AF:

0.0414

Gnomad SAS

AF:

0.130

Gnomad FIN

AF:

0.155

Gnomad MID

AF:

0.0791

Gnomad NFE

AF:

0.218

Gnomad OTH

AF:

0.142

GnomAD3 exomes

AF:

0.173

AC:

42022

AN:

243204

Hom.:

4105

AF XY:

0.173

AC XY:

22829

AN XY:

131994

show subpopulations

Gnomad AFR exome

AF:

0.0953

Gnomad AMR exome

AF:

0.172

Gnomad ASJ exome

AF:

0.217

Gnomad EAS exome

AF:

0.0371

Gnomad SAS exome

AF:

0.125

Gnomad FIN exome

AF:

0.153

Gnomad NFE exome

AF:

0.218

Gnomad OTH exome

AF:

0.190

GnomAD4 exome

AF:

0.204

AC:

296864

AN:

1457624

Hom.:

31767

Cov.:

AF XY:

0.202

AC XY:

146109

AN XY:

724800

show subpopulations

Gnomad4 AFR exome

AF:

0.0924

Gnomad4 AMR exome

AF:

0.171

Gnomad4 ASJ exome

AF:

0.214

Gnomad4 EAS exome

AF:

0.0351

Gnomad4 SAS exome

AF:

0.130

Gnomad4 FIN exome

AF:

0.154

Gnomad4 NFE exome

AF:

0.223

Gnomad4 OTH exome

AF:

0.187

GnomAD4 genome

AF:

0.165

AC:

25162

AN:

152160

Hom.:

2322

Cov.:

AF XY:

0.160

AC XY:

11905

AN XY:

74396

show subpopulations

Gnomad4 AFR

AF:

0.0979

Gnomad4 AMR

AF:

0.161

Gnomad4 ASJ

AF:

0.214

Gnomad4 EAS

AF:

0.0413

Gnomad4 SAS

AF:

0.130

Gnomad4 FIN

AF:

0.155

Gnomad4 NFE

AF:

0.218

Gnomad4 OTH

AF:

0.140

Alfa

AF:

0.201

Hom.:

4743

Bravo

AF:

0.162

TwinsUK

AF:

0.221

AC:

820

ALSPAC

AF:

0.238

AC:

918

ESP6500AA

AF:

0.0942

AC:

413

ESP6500EA

AF:

0.221

AC:

1897

ExAC

AF:

0.172

AC:

20732

Asia WGS

AF:

0.0930

AC:

324

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 02, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 12610512, 14551916) -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Transient Neonatal Diabetes, Dominant/Recessive

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Maturity onset diabetes mellitus in young

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive DOPA responsive dystonia

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Maturity-onset diabetes of the young type 10

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Hypoinsulinemia

Other:1

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: association

Review Status: no assertion criteria provided

Collection Method: research

Mutations in this gene can cause early onset diabetes mellitus which is insulin dependent. Poor response to sulfonylureas, as this mutation can cause beta cell destruction. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.15

CADD

Benign

0.51

DANN

Benign

0.94

Eigen

Benign

-0.99

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.010

LIST_S2

Benign

0.37

MetaRNN

Benign

0.0048

MetaSVM

Benign

-1.0

PROVEAN

Benign

2.3

REVEL

Benign

0.23

Sift

Benign

0.046

ClinPred

0.0080

GERP RS

-0.36

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