ENST00000729705.1:n.174+2388G>T

Variant names:

• chr11-2161302-G-T
• rs748749585
• ENST00000729705.1:n.174+2388G>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 12P and 1B. PS3 PP5_Very_Strong BP4

The ENST00000729705.1(ENSG00000295384):​n.174+2388G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000134 in 313,286 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV005888155: The most pronounced variant effect results in a significant reduction in promoter activity (Garin_2010). PMID:25755231; SCV001793392: Published functional studies demonstrate a damaging effect on INS promoter activity (Garin et al., 2010); PMID:20301620, 20133622, 21592955, 20938745, 32656923, 34426871, 21808142, 33409956, 25755231; SCV002067469: Functional studies demonstrated that this variant significantly impaired INS transcription in vitro (PMID 20133622).".

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: ENSG00000295384 ENST00000729705.1 intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: -2.01
• Publications: 15 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: Pathogenic. The variant received 11 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV005888155: The most pronounced variant effect results in a significant reduction in promoter activity (Garin_2010). PMID:25755231; SCV001793392: Published functional studies demonstrate a damaging effect on INS promoter activity (Garin et al., 2010); PMID: 20301620, 20133622, 21592955, 20938745, 32656923, 34426871, 21808142, 33409956, 25755231; SCV002067469: Functional studies demonstrated that this variant significantly impaired INS transcription in vitro (PMID 20133622).
• PP5: Variant 11-2161302-G-T is Pathogenic according to our data. Variant chr11-2161302-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 431442.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86). . Strength limited to SUPPORTING due to the PP5.

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.-152C>A		upstream_gene	N/A	NP_000198.1	P01308-1
	INS-IGF2	NM_001042376.3		c.-152C>A		upstream_gene	N/A	NP_001035835.1	F8WCM5-1
	INS	NM_001185097.2		c.-178C>A		upstream_gene	N/A	NP_001172026.1	I3WAC9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENSG00000295384	ENST00000729705.1		n.174+2388G>T		intron	N/A
	ENSG00000295384	ENST00000729706.1		n.225+2388G>T		intron	N/A
	INS	ENST00000381330.5	TSL:1 MANE Select	c.-152C>A		upstream_gene	N/A	ENSP00000370731.5	P01308-1

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152022 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000435

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000589

Gnomad OTH AF: 0.000957

GnomAD4 exome AF: 0.000105 AC: 17 AN: 161264 Hom.: 0 Cov.: 0 AF XY: 0.000123 AC XY: 10 AN XY: 81586

African (AFR) AF: 0.000160 AC: 1 AN: 6260

American (AMR) AF: 0.000140 AC: 1 AN: 7122

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5886

East Asian (EAS) AF: 0.0000764 AC: 1 AN: 13088

South Asian (SAS) AF: 0.000200 AC: 2 AN: 10002

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8768

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 800

European-Non Finnish (NFE) AF: 0.000111 AC: 11 AN: 99244

Other (OTH) AF: 0.0000991 AC: 1 AN: 10094

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152022 Hom.: 0 Cov.: 33 AF XY: 0.000189 AC XY: 14 AN XY: 74252

African (AFR) AF: 0.000435 AC: 18 AN: 41390

American (AMR) AF: 0.0000655 AC: 1 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000589 AC: 4 AN: 67942

Other (OTH) AF: 0.000957 AC: 2 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000212

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
1	-	-	Hyperproinsulinemia;C1852092:Type 1 diabetes mellitus 2;C3150617:Maturity-onset diabetes of the young type 10;C5394307:Diabetes mellitus, permanent neonatal 4 (1)
1	-	-	INS-related disorder (1)
1	-	-	Permanent neonatal diabetes mellitus (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.64
DANN	Benign	0.86
PhyloP100		-2.0
PromoterAI		-0.013	Neutral
Mutation Taster		=117/183	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs748749585; hg19: chr11-2182532;