11-2159830-T-G

Variant names:

• chr11-2159830-T-G
• rs3842753
• ENST00000381330:c.*22A>C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: 1.05

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: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]

ACMG classification

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: {Benign=10, Uncertain_significance=1}. 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	c.*22A>C		3_prime_UTR_variant	Exon 3 of 3	ENST00000381330.5	NP_000198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INS	ENST00000381330	c.*22A>C		3_prime_UTR_variant	Exon 3 of 3	1	NM_000207.3	ENSP00000370731.5
INS-IGF2	ENST00000397270.1	c.187+955A>C		intron_variant	Intron 2 of 4	1		ENSP00000380440.1

Frequencies

GnomAD3 genomes AF: 0.610 AC: 92705 AN: 151854 Hom.: 31998 Cov.: 33

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

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.: 40 AF XY: 0.725 AC XY: 524628 AN XY: 723788

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.: 33 AF XY: 0.623 AC XY: 46299 AN XY: 74286

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:1 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Mar 31, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Maturity-onset diabetes of the young type 10 Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diabetes mellitus type 1 Uncertain:1

-

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

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

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hyperproinsulinemia Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Transient Neonatal Diabetes, Dominant/Recessive Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Type 1 diabetes mellitus 2 Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: 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: 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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.34	T
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	N
LIST_S2	Benign	0.15	T
MetaRNN	Benign	8.3e-7	T
MetaSVM	Benign	-0.89	T
PROVEAN	Benign	0.19	N
REVEL	Benign	0.16
Sift	Benign	0.23	T
ClinPred		0.0091	T
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

Other links and lift over

dbSNP: rs3842753; hg19: chr11-2181060;