rs563630291

Variant names:

• chr11-2161296-TG-T
• rs563630291
• NM_000207.3:c.-147delC

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_000207.3(INS):​c.-147delC variant causes a upstream gene 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: INS NM_000207.3 upstream_gene
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.66

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 -16 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 id is 435506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00966 (1469/152128) while in subpopulation NFE AF= 0.0138 (939/67936). AF 95% confidence interval is 0.0131. There are 10 homozygotes in gnomad4. There are 764 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1469 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INS	NM_000207.3	c.-147delC		upstream_gene_variant		ENST00000381330.5	NP_000198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INS	ENST00000381330.5	c.-147delC		upstream_gene_variant		1	NM_000207.3	ENSP00000370731.5
INS-IGF2	ENST00000397270.1	c.-147delC		upstream_gene_variant		1		ENSP00000380440.1

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

Gnomad4 AFR exome AF: 0.00238

Gnomad4 AMR exome AF: 0.00497

Gnomad4 ASJ exome AF: 0.000333

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00535

Gnomad4 FIN exome AF: 0.0260

Gnomad4 NFE exome AF: 0.0134

Gnomad4 OTH exome AF: 0.00988

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

Gnomad4 AFR AF: 0.00210

Gnomad4 AMR AF: 0.00713

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.0259

Gnomad4 NFE AF: 0.0138

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.0110 Hom.: 3

Bravo AF: 0.00762

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

INS-IGF2: BS1, BS2 -

Mar 25, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Oct 31, 2016

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neonatal insulin-dependent diabetes mellitus Benign:1

-

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

Mutations in INS gene can cause early onset diabetes mellitus which is insulin dependent. May have poor response to sulfonylureas, as this mutation can cause beta cell destruction. However no sufficient evidence is found to ascertain the role of this particular variant rs563630291, yet. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs563630291; hg19: chr11-2182526;