11-2160774-A-G

Position:

• chr11-2160774-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000207.3(INS):​c.187+11T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.988 in 1,610,624 control chromosomes in the GnomAD database, including 787,793 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.94 (67638 hom., cov: 35)
  • Exomes 𝑓: 0.99 (720155 hom.)
• Consequence: INS NM_000207.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.166

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]

INS-IGF2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 11-2160774-A-G is Benign according to our data. Variant chr11-2160774-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 255532.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2160774-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INS	NM_000207.3	c.187+11T>C		intron_variant		ENST00000381330.5	NP_000198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INS	ENST00000381330.5	c.187+11T>C		intron_variant		1	NM_000207.3	ENSP00000370731.5
INS-IGF2	ENST00000397270.1	c.187+11T>C		intron_variant		1		ENSP00000380440.1

Frequencies

GnomAD3 genomes AF: 0.938 AC: 142735 AN: 152154 Hom.: 67600 Cov.: 35

Gnomad AFR AF: 0.784

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.979

Gnomad ASJ AF: 0.998

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.999

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.981

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.956

GnomAD3 exomes AF: 0.984 AC: 242627 AN: 246646 Hom.: 119691 AF XY: 0.988 AC XY: 132592 AN XY: 134236

Gnomad AFR exome AF: 0.780

Gnomad AMR exome AF: 0.990

Gnomad ASJ exome AF: 0.998

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 0.999

Gnomad OTH exome AF: 0.992

GnomAD4 exome AF: 0.993 AC: 1448313 AN: 1458352 Hom.: 720155 Cov.: 62 AF XY: 0.994 AC XY: 720715 AN XY: 725112

Gnomad4 AFR exome AF: 0.763

Gnomad4 AMR exome AF: 0.988

Gnomad4 ASJ exome AF: 0.998

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.999

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 1.00

Gnomad4 OTH exome AF: 0.985

GnomAD4 genome AF: 0.938 AC: 142824 AN: 152272 Hom.: 67638 Cov.: 35 AF XY: 0.940 AC XY: 70000 AN XY: 74448

Gnomad4 AFR AF: 0.784

Gnomad4 AMR AF: 0.979

Gnomad4 ASJ AF: 0.998

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.999

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 0.999

Gnomad4 OTH AF: 0.956

Alfa AF: 0.967 Hom.: 19708

Bravo AF: 0.929

Asia WGS AF: 0.988 AC: 3436 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 02, 2017	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Type 2 diabetes mellitus Benign:1

Benign, no assertion criteria provided

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

-

- -

Hyperproinsulinemia;C1852092:Type 1 diabetes mellitus 2;C3150617:Maturity-onset diabetes of the young type 10;C5394307:Diabetes mellitus, permanent neonatal 4 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 04, 2022

- -

Transient Neonatal Diabetes, Dominant/Recessive Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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

- -

Maturity-onset diabetes of the young type 10 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.10
DANN	Benign	0.52

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: rs5506; hg19: chr11-2182004;