11-2159830-T-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_000207.3(INS):c.*22A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.71 in 1,607,734 control chromosomes in the GnomAD database, including 415,760 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.61 ( 32006 hom., cov: 33)

Exomes 𝑓: 0.72 ( 383754 hom. )

Consequence

INS
NM_000207.3 3_prime_UTR

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:10

Conservation

PhyloP100: 1.05

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=8.279031E-7).

BP6

Variant 11-2159830-T-G is Benign according to our data. Variant chr11-2159830-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 304051.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=10}. Variant chr11-2159830-T-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.927 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INS	NM_000207.3 link	c.*22A>C		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.*22A>C		3_prime_UTR_variant	Exon 3 of 3	1	NM_000207.3	ENSP00000370731.5		P01308-1
INS-IGF2	ENST00000397270.1 link	c.187+955A>C		intron_variant	Intron 2 of 4	1		ENSP00000380440.1		F8WCM5-1

Frequencies

GnomAD3 genomes

AF:

0.610

AC:

92705

AN:

151854

Hom.:

31998

Cov.:

show subpopulations

Gnomad AFR

AF:

0.260

Gnomad AMI

AF:

0.662

Gnomad AMR

AF:

0.725

Gnomad ASJ

AF:

0.710

Gnomad EAS

AF:

0.949

Gnomad SAS

AF:

0.831

Gnomad FIN

AF:

0.793

Gnomad MID

AF:

0.793

Gnomad NFE

AF:

0.719

Gnomad OTH

AF:

0.671

GnomAD3 exomes

AF:

0.733

AC:

176653

AN:

240868

Hom.:

67320

AF XY:

0.744

AC XY:

97323

AN XY:

130744

show subpopulations

Gnomad AFR exome

AF:

0.242

Gnomad AMR exome

AF:

0.768

Gnomad ASJ exome

AF:

0.701

Gnomad EAS exome

AF:

0.953

Gnomad SAS exome

AF:

0.833

Gnomad FIN exome

AF:

0.797

Gnomad NFE exome

AF:

0.719

Gnomad OTH exome

AF:

0.736

GnomAD4 exome

AF:

0.720

AC:

1048832

AN:

1455762

Hom.:

383754

Cov.:

AF XY:

0.725

AC XY:

524628

AN XY:

723788

show subpopulations

Gnomad4 AFR exome

AF:

0.241

Gnomad4 AMR exome

AF:

0.762

Gnomad4 ASJ exome

AF:

0.705

Gnomad4 EAS exome

AF:

0.958

Gnomad4 SAS exome

AF:

0.827

Gnomad4 FIN exome

AF:

0.793

Gnomad4 NFE exome

AF:

0.713

Gnomad4 OTH exome

AF:

0.716

GnomAD4 genome

AF:

0.610

AC:

92730

AN:

151972

Hom.:

32006

Cov.:

AF XY:

0.623

AC XY:

46299

AN XY:

74286

show subpopulations

Gnomad4 AFR

AF:

0.260

Gnomad4 AMR

AF:

0.725

Gnomad4 ASJ

AF:

0.710

Gnomad4 EAS

AF:

0.949

Gnomad4 SAS

AF:

0.831

Gnomad4 FIN

AF:

0.793

Gnomad4 NFE

AF:

0.719

Gnomad4 OTH

AF:

0.675

Alfa

AF:

0.665

Hom.:

16293

Bravo

AF:

0.587

TwinsUK

AF:

0.714

AC:

2648

ALSPAC

AF:

0.697

AC:

2688

ESP6500AA

AF:

0.269

AC:

1174

ESP6500EA

AF:

0.690

AC:

5919

ExAC

AF:

0.716

AC:

85906

Asia WGS

AF:

0.842

AC:

2928

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:10

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 31, 2019	- -

Maturity-onset diabetes of the young type 10

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

Diabetes mellitus type 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Potent mutations in this gene can cause early onset diabetes mellitus which is insulin dependent. May have poor response to sulfonylureas, as potent mutations in INS gene can cause beta cell destruction. rs3842753 variant, could be a contributing factor to the increased risk of T1D development, as it might increase insulin production. However more evidence are required to ascertain the role of this particular variant rs3842753 in Type 1 diabetes mellitus . -

Diabetes mellitus, permanent neonatal 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Hyperproinsulinemia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Transient Neonatal Diabetes, Dominant/Recessive

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Type 1 diabetes mellitus 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Maturity onset diabetes mellitus in young

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Autosomal recessive DOPA responsive dystonia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.12

CADD

Benign

0.70

DANN

Benign

0.45

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.00072

LIST_S2

Benign

0.15

MetaRNN

Benign

8.3e-7

MetaSVM

Benign

-0.89

PROVEAN

Benign

0.19

REVEL

Benign

0.16

Sift

Benign

0.23

ClinPred

0.0091

GERP RS

-3.8

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