11-2160994-A-T

Variant names:

• chr11-2160994-A-T
• rs689
• ENST00000397262.5:c.-23T>A

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.-17-6T>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.71 in 1,609,954 control chromosomes in the GnomAD database, including 415,985 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.61 (32035 hom., cov: 35)
  • Exomes 𝑓: 0.72 (383950 hom.)
• Consequence: INS NM_000207.3 splice_region, intron
• Scores: Splicing: ADA: 0.1228
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0740

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 11-2160994-A-T is Benign according to our data. Variant chr11-2160994-A-T is described in ClinVar as [Benign]. Clinvar id is 304059.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.926 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INS	NM_000207.3	c.-17-6T>A		splice_region_variant, intron_variant	Intron 1 of 2	ENST00000381330.5	NP_000198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INS	ENST00000381330.5	c.-17-6T>A		splice_region_variant, intron_variant	Intron 1 of 2	1	NM_000207.3	ENSP00000370731.5
INS-IGF2	ENST00000397270.1	c.-17-6T>A		splice_region_variant, intron_variant	Intron 1 of 4	1		ENSP00000380440.1

Frequencies

GnomAD3 genomes AF: 0.611 AC: 92830 AN: 152032 Hom.: 32028 Cov.: 35

Gnomad AFR AF: 0.263

Gnomad AMI AF: 0.666

Gnomad AMR AF: 0.725

Gnomad ASJ AF: 0.709

Gnomad EAS AF: 0.947

Gnomad SAS AF: 0.831

Gnomad FIN AF: 0.792

Gnomad MID AF: 0.788

Gnomad NFE AF: 0.719

Gnomad OTH AF: 0.669

GnomAD3 exomes AF: 0.734 AC: 178240 AN: 242726 Hom.: 67953 AF XY: 0.745 AC XY: 98674 AN XY: 132380

Gnomad AFR exome AF: 0.247

Gnomad AMR exome AF: 0.769

Gnomad ASJ exome AF: 0.703

Gnomad EAS exome AF: 0.953

Gnomad SAS exome AF: 0.833

Gnomad FIN exome AF: 0.797

Gnomad NFE exome AF: 0.720

Gnomad OTH exome AF: 0.737

GnomAD4 exome AF: 0.720 AC: 1049977 AN: 1457804 Hom.: 383950 Cov.: 61 AF XY: 0.725 AC XY: 525501 AN XY: 725156

Gnomad4 AFR exome AF: 0.245

Gnomad4 AMR exome AF: 0.762

Gnomad4 ASJ exome AF: 0.705

Gnomad4 EAS exome AF: 0.959

Gnomad4 SAS exome AF: 0.827

Gnomad4 FIN exome AF: 0.792

Gnomad4 NFE exome AF: 0.713

Gnomad4 OTH exome AF: 0.716

GnomAD4 genome AF: 0.610 AC: 92854 AN: 152150 Hom.: 32035 Cov.: 35 AF XY: 0.624 AC XY: 46388 AN XY: 74386

Gnomad4 AFR AF: 0.263

Gnomad4 AMR AF: 0.725

Gnomad4 ASJ AF: 0.709

Gnomad4 EAS AF: 0.948

Gnomad4 SAS AF: 0.831

Gnomad4 FIN AF: 0.792

Gnomad4 NFE AF: 0.719

Gnomad4 OTH AF: 0.673

Alfa AF: 0.676 Hom.: 6698

Bravo AF: 0.588

Asia WGS AF: 0.841 AC: 2925 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

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: 16380501, 17327440, 22357962, 20628762) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 24, 2017

Athena Diagnostics

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

- -

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

- -

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

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.2
DANN	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.12
dbscSNV1_RF	Benign	0.39
SpliceAI score (max)		0.38		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.38		Position offset: -6

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs689; hg19: chr11-2182224;