rs797045623

Variant names:

• chr11-2160028-C-T
• rs797045623
• NM_000207.3:c.188-31G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_000207.3(INS):​c.188-31G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely risk allele (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: INS NM_000207.3 intron
• Clinical Significance: Pathogenic/Likely risk allele criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 0.540
• Publications: 10 publications found

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]

ENSG00000295384 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 11-2160028-C-T is Pathogenic according to our data. Variant chr11-2160028-C-T is described in ClinVar as Pathogenic/Likely_risk_allele. ClinVar VariationId is 211186.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000207.3. 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.188-31G>A		intron	N/A	NP_000198.1
	INS-IGF2	NM_001042376.3		c.187+757G>A		intron	N/A	NP_001035835.1
	INS	NM_001185097.2		c.188-31G>A		intron	N/A	NP_001172026.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INS	ENST00000381330.5	TSL:1 MANE Select	c.188-31G>A		intron	N/A	ENSP00000370731.5
	INS-IGF2	ENST00000397270.1	TSL:1	c.187+757G>A		intron	N/A	ENSP00000380440.1
	INS	ENST00000250971.7	TSL:1	c.188-31G>A		intron	N/A	ENSP00000250971.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 167436 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1406148 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 695738

African (AFR) AF: 0.00 AC: 0 AN: 32794

American (AMR) AF: 0.00 AC: 0 AN: 37370

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25340

East Asian (EAS) AF: 0.00 AC: 0 AN: 37640

South Asian (SAS) AF: 0.00 AC: 0 AN: 80698

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39636

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4480

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1089622

Other (OTH) AF: 0.00 AC: 0 AN: 58568

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000345 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely risk allele

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	not provided (5)
2	-	-	Permanent neonatal diabetes mellitus (2)
-	-	-	Diabetes mellitus, permanent neonatal 4 (1)
-	-	-	Neonatal insulin-dependent diabetes mellitus (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	17
DANN	Benign	0.38
PhyloP100		0.54
BranchPoint Hunter		3.0
Mutation Taster		=5/95	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.98		Position offset: -2
DS_AL_spliceai		0.75		Position offset: -31

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

Other links and lift over

dbSNP: rs797045623; hg19: chr11-2181258;