rs563630291

Variant names:

• chr11-2161296-TG-T
• rs563630291
• ENST00000729705.1:n.174+2383delG

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The ENST00000729705.1(ENSG00000295384):​n.174+2383delG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0104 in 318,044 control chromosomes in the GnomAD database, including 28 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0097 (10 hom., cov: 33)
  • Exomes 𝑓: 0.011 (18 hom.)
• Consequence: ENSG00000295384 ENST00000729705.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.66
• Publications: 0 publications found

Genes affected

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-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

Our verdict: Benign. The variant received -12 ACMG points.

• BP6: Variant 11-2161296-TG-T is Benign according to our data. Variant chr11-2161296-TG-T is described in ClinVar as Benign. ClinVar VariationId is 435506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 10 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000729705.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INS	NM_000207.3	MANE Select	c.-147delC		upstream_gene	N/A	NP_000198.1
	INS-IGF2	NM_001042376.3		c.-147delC		upstream_gene	N/A	NP_001035835.1
	INS	NM_001185097.2		c.-173delC		upstream_gene	N/A	NP_001172026.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENSG00000295384	ENST00000729705.1		n.174+2383delG		intron	N/A
	ENSG00000295384	ENST00000729706.1		n.225+2383delG		intron	N/A
	INS	ENST00000381330.5	TSL:1 MANE Select	c.-147delC		upstream_gene	N/A	ENSP00000370731.5

Frequencies

GnomAD3 genomes AF: 0.00967 AC: 1470 AN: 152010 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.00210

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.00714

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.0259

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0138

Gnomad OTH AF: 0.00860

GnomAD4 exome AF: 0.0110 AC: 1833 AN: 165916 Hom.: 18 Cov.: 0 AF XY: 0.0109 AC XY: 913 AN XY: 83750

African (AFR) AF: 0.00238 AC: 15 AN: 6304

American (AMR) AF: 0.00497 AC: 34 AN: 6846

Ashkenazi Jewish (ASJ) AF: 0.000333 AC: 2 AN: 6000

East Asian (EAS) AF: 0.00 AC: 0 AN: 13558

South Asian (SAS) AF: 0.00535 AC: 52 AN: 9726

European-Finnish (FIN) AF: 0.0260 AC: 246 AN: 9456

Middle Eastern (MID) AF: 0.00120 AC: 1 AN: 832

European-Non Finnish (NFE) AF: 0.0134 AC: 1380 AN: 102766

Other (OTH) AF: 0.00988 AC: 103 AN: 10428

GnomAD4 genome AF: 0.00966 AC: 1469 AN: 152128 Hom.: 10 Cov.: 33 AF XY: 0.0103 AC XY: 764 AN XY: 74384

African (AFR) AF: 0.00210 AC: 87 AN: 41512

American (AMR) AF: 0.00713 AC: 109 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4822

European-Finnish (FIN) AF: 0.0259 AC: 275 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0138 AC: 939 AN: 67936

Other (OTH) AF: 0.00851 AC: 18 AN: 2114

Alfa AF: 0.0110 Hom.: 3

Bravo AF: 0.00762

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Neonatal insulin-dependent diabetes mellitus (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-2.7
Mutation Taster		=299/1	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs563630291; hg19: chr11-2182526;