Genetic Variant ENST00000729705.1:n.174+2388G>C (chr11-2161302-G-C) – ACMG Classification: Pathogenic (13 pts)

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 14P and 1B. PS3PM2PP5_Very_StrongBP4

The ENST00000729705.1(ENSG00000295384):n.174+2388G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000287 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 Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV003842452: Published functional studies demonstrate a damaging effect on promoter activity (Garin et al., 2010" and additional evidence is available in ClinVar.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000037 ( 0 hom. )

Consequence

ENSG00000295384
ENST00000729705.1 intron

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6B:1O:1

Conservation

PhyloP100: -2.01

Publications

15 publications found

Variant links:

Genes affected

ENSG00000295384 (HGNC:):

ENSG00000295384 links:

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 links:

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]

INS-IGF2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 13 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV003842452: Published functional studies demonstrate a damaging effect on promoter activity (Garin et al., 2010; Bonnefond et al., 2011); SCV004294058: Experimental studies have shown that this variant affects INS function (PMID: 21592955).

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-2161302-G-C is Pathogenic according to our data. Variant chr11-2161302-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 431443.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88). . 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
INS	NM_000207.3	MANE Select	c.-152C>G	upstream_gene	N/A	NP_000198.1	P01308-1
INS-IGF2	NM_001042376.3		c.-152C>G	upstream_gene	N/A	NP_001035835.1	F8WCM5-1
INS	NM_001185097.2		c.-178C>G	upstream_gene	N/A	NP_001172026.1	I3WAC9

Ensembl Transcripts

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

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152022

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000372

AC:

AN:

161264

Hom.:

Cov.:

AF XY:

0.0000245

AC XY:

AN XY:

81586

show subpopulations

African (AFR)

AF:

0.000160

AC:

AN:

6260

American (AMR)

AF:

0.00

AC:

AN:

7122

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

5886

East Asian (EAS)

AF:

0.0000764

AC:

AN:

13088

South Asian (SAS)

AF:

0.00

AC:

AN:

10002

European-Finnish (FIN)

AF:

0.000342

AC:

AN:

8768

Middle Eastern (MID)

AF:

0.00

AC:

AN:

800

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

99244

Other (OTH)

AF:

0.0000991

AC:

AN:

10094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152022

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74252

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41390

American (AMR)

AF:

0.0000655

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67942

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000540

Hom.:

Bravo

AF:

0.00000756

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Amyotrophic lateral sclerosis, susceptibility to, 24 (1)

Diabetes mellitus (1)

Diabetes mellitus, permanent neonatal 4 (1)

Hyperproinsulinemia;C1852092:Type 1 diabetes mellitus 2;C3150617:Maturity-onset diabetes of the young type 10;C5394307:Diabetes mellitus, permanent neonatal 4 (1)

not specified (1)

Permanent neonatal diabetes mellitus (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.59

(source)

DANN

Benign

0.74

PhyloP100

-2.0

PromoterAI

-0.016

Neutral

(source)

Mutation Taster

=117/183

disease causing (ClinVar)

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over