chr19-7143063-G-A
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Variant summary
Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2
The NM_000208.4(INSR):c.2295C>T(p.Gly765=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000792 in 1,614,158 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00064 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00081 ( 2 hom. )
Consequence
INSR
NM_000208.4 synonymous
NM_000208.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -1.49
Genes affected
INSR (HGNC:6091): (insulin receptor) This gene encodes a member of the receptor tyrosine kinase family of proteins. The encoded preproprotein is proteolytically processed to generate alpha and beta subunits that form a heterotetrameric receptor. Binding of insulin or other ligands to this receptor activates the insulin signaling pathway, which regulates glucose uptake and release, as well as the synthesis and storage of carbohydrates, lipids and protein. Mutations in this gene underlie the inherited severe insulin resistance syndromes including type A insulin resistance syndrome, Donohue syndrome and Rabson-Mendenhall syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2015]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -14 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.81).
BP6
Variant 19-7143063-G-A is Benign according to our data. Variant chr19-7143063-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 330462.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=1, Uncertain_significance=3}. Variant chr19-7143063-G-A is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=-1.49 with no splicing effect.
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000644 (98/152276) while in subpopulation SAS AF= 0.0029 (14/4824). AF 95% confidence interval is 0.00175. There are 0 homozygotes in gnomad4. There are 48 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 2 AD,AR gene
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| INSR | NM_000208.4 | c.2295C>T | p.Gly765= | synonymous_variant | 12/22 | ENST00000302850.10 | NP_000199.2 | |
| INSR | NM_001079817.3 | c.2259C>T | p.Gly753= | synonymous_variant | 11/21 | NP_001073285.1 | ||
| INSR | XM_011527988.3 | c.2295C>T | p.Gly765= | synonymous_variant | 12/22 | XP_011526290.2 | ||
| INSR | XM_011527989.4 | c.2259C>T | p.Gly753= | synonymous_variant | 11/21 | XP_011526291.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| INSR | ENST00000302850.10 | c.2295C>T | p.Gly765= | synonymous_variant | 12/22 | 1 | NM_000208.4 | ENSP00000303830 | A2 | |
| INSR | ENST00000341500.9 | c.2259C>T | p.Gly753= | synonymous_variant | 11/21 | 1 | ENSP00000342838 | P3 | ||
| INSR | ENST00000597211.1 | upstream_gene_variant | 3 |
Frequencies
GnomAD3 genomes 0.000644 AC: 98AN: 152158Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000792 AC: 199AN: 251140Hom.: 1 AF XY: 0.00102 AC XY: 139AN XY: 135790
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GnomAD4 exome AF: 0.000807 AC: 1180AN: 1461882Hom.: 2 Cov.: 32 AF XY: 0.000872 AC XY: 634AN XY: 727246
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GnomAD4 genome 0.000644 AC: 98AN: 152276Hom.: 0 Cov.: 32 AF XY: 0.000645 AC XY: 48AN XY: 74450
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:7
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Benign:3
| Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 02, 2023 | - - |
not specified Benign:2
| Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Dec 08, 2015 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Sep 07, 2018 | - - |
Insulin-resistant diabetes mellitus AND acanthosis nigricans Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Rabson-Mendenhall syndrome Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Leprechaunism syndrome Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Hyperinsulinism due to INSR deficiency Benign:1
| Likely benign, criteria provided, single submitter | research | Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic | - | Potent mutations in INSR gene can lead to insulin resistance, which presents as impaired glucose tolerance, early onset type 2 diabetes, post prandial hyperglycemia and increased insulin requirement in type 1 diabetes. These mutations in INSR gene can also predispose to coronary artery disease, metabolic syndrome, polycystic ovarian disease and non alcoholic fatty liver disease.However, the role of this particular variantrs142654992 with early onset diabetes mellitus is yet to be ascertained. - |
INSR-related disorder Benign:1
| Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 12, 2024 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Name
Calibrated prediction
Score
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at