11-2161302-G-C

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 10P and 1B. PM2PP5_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 (★★).

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: Likely_pathogenic. The variant received 9 ACMG points.

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
INS	NM_000207.3	MANE Select	c.-152C>G	upstream_gene	N/A	NP_000198.1
INS-IGF2	NM_001042376.3		c.-152C>G	upstream_gene	N/A	NP_001035835.1
INS	NM_001185097.2		c.-178C>G	upstream_gene	N/A	NP_001172026.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
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

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

Significance: Pathogenic

Submissions summary: Pathogenic:6Benign:1Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Mar 14, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant often referred to as c.-331 C>G using alternate nomenclature; Published functional studies demonstrate a damaging effect on promoter activity (Garin et al., 2010; Bonnefond et al., 2011); A different variant at this position (c.-152 C>A) has been reported as likely pathogenic at GeneDx in association with neonatal diabetes; Nucleotide substitution has no predicted effect on splicing and is not conserved across species; This variant is associated with the following publications: (PMID: 29305569, 24622368, 32252216, 21592955, 20133622, 29183106, 31441606, 32656923, 34101350, 35140529, 33852861, 34458657)

Oct 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant occurs in a non-coding region of the INS gene. It does not change the encoded amino acid sequence of the INS protein. This variant is present in population databases (rs748749585, gnomAD 0.1%). This variant has been observed in individuals with neonatal diabetes (PMID: 20133622). It has also been observed to segregate with disease in related individuals. This variant is also known as c.-331 C>G. ClinVar contains an entry for this variant (Variation ID: 431443). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects INS function (PMID: 21592955). For these reasons, this variant has been classified as Pathogenic.

not specified

Pathogenic:1

Aug 20, 2019

Genetic Services Laboratory, University of Chicago

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Pathogenic:1

May 25, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Diabetes mellitus

Pathogenic:1

Oct 04, 2024

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

PS3,PS4,PM2

Amyotrophic lateral sclerosis, susceptibility to, 24

Pathogenic:1

Sep 10, 2025

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Diabetes mellitus, permanent neonatal 4

Benign:1

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance:Likely benign

Review Status:flagged submission

Collection Method:research

Potent mutations in the INS gene can cause early onset diabetes mellitus which is insulin dependent. May have poor response to sulfonylureas, mutations in this gene can cause beta cell destruction.rs748749585 variant is Prevalent in patients with Neonatal diabetes mellitus. However, the role of this particular variant is yet to be ascertained

Permanent neonatal diabetes mellitus

Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over