rs3842755

Variant names:

• chr11-2159566-C-A
• rs3842755
• ENST00000397270.1:c.187+1219G>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000397270.1(INS-IGF2):​c.187+1219G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.172 in 152,172 control chromosomes in the GnomAD database, including 2,425 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.17 (2425 hom., cov: 32)
• Consequence: INS-IGF2 ENST00000397270.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -4.76
• Publications: 7 publications found

Genes affected

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]

ENSG00000295384 (HGNC:):

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 Gene-Disease associations (from GenCC):

• monogenic diabetes

  Inheritance: AD, AR Classification: DEFINITIVE Submitted by: ClinGen
• hyperproinsulinemia

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• maturity-onset diabetes of the young type 10

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• permanent neonatal diabetes mellitus

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• type 1 diabetes mellitus 2

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• diabetes mellitus, permanent neonatal 4

  Inheritance: AR, AD Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• transient neonatal diabetes mellitus

  Inheritance: AR, AD Classification: STRONG Submitted by: Genomics England PanelApp
• maturity-onset diabetes of the young

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 11-2159566-C-A is Benign according to our data. Variant chr11-2159566-C-A is described in ClinVar as Benign. ClinVar VariationId is 1275239.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.215 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000397270.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INS-IGF2	NM_001042376.3		c.187+1219G>T		intron	N/A	NP_001035835.1
	INS-IGF2	NR_003512.4		n.246+1219G>T		intron	N/A
	INS	NM_000207.3	MANE Select	c.*286G>T		downstream_gene	N/A	NP_000198.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INS-IGF2	ENST00000397270.1	TSL:1	c.187+1219G>T		intron	N/A	ENSP00000380440.1
	INS-IGF2	ENST00000356578.8	TSL:5	n.187+1219G>T		intron	N/A	ENSP00000348986.4
	ENSG00000295384	ENST00000729705.1		n.174+652C>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.172 AC: 26167 AN: 152056 Hom.: 2424 Cov.: 32

Gnomad AFR AF: 0.117

Gnomad AMI AF: 0.318

Gnomad AMR AF: 0.173

Gnomad ASJ AF: 0.215

Gnomad EAS AF: 0.0409

Gnomad SAS AF: 0.129

Gnomad FIN AF: 0.155

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.218

Gnomad OTH AF: 0.149

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.172 AC: 26167 AN: 152172 Hom.: 2425 Cov.: 32 AF XY: 0.167 AC XY: 12403 AN XY: 74410

African (AFR) AF: 0.117 AC: 4860 AN: 41516

American (AMR) AF: 0.173 AC: 2641 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.215 AC: 745 AN: 3472

East Asian (EAS) AF: 0.0408 AC: 211 AN: 5172

South Asian (SAS) AF: 0.129 AC: 620 AN: 4818

European-Finnish (FIN) AF: 0.155 AC: 1641 AN: 10600

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.218 AC: 14829 AN: 67982

Other (OTH) AF: 0.147 AC: 310 AN: 2112

Alfa AF: 0.189 Hom.: 388

Bravo AF: 0.170

Asia WGS AF: 0.0960 AC: 334 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 25, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.039
DANN	Benign	0.76
PhyloP100		-4.8
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3842755; hg19: chr11-2180796;