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rs2229433

chr19-7132282-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000208.4(INSR):c.2718T>C(p.Ala906=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00156 in 1,614,142 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0083 ( 19 hom., cov: 31)
Exomes 𝑓: 0.00086 ( 18 hom. )

Consequence

INSR
NM_000208.4 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.283
Variant links:
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 -21 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.87).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 19-7132282-A-G is Benign according to our data. Variant chr19-7132282-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 330451.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-0.283 with no splicing effect.
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00825 (1257/152276) while in subpopulation AFR AF= 0.0284 (1181/41566). AF 95% confidence interval is 0.0271. There are 19 homozygotes in gnomad4. There are 603 alleles in male gnomad4 subpopulation. This position pass quality control queck.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High Homozygotes in GnomAd at 19 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
INSRNM_000208.4 linkuse as main transcriptc.2718T>C p.Ala906= synonymous_variant 14/22 ENST00000302850.10
INSRNM_001079817.3 linkuse as main transcriptc.2682T>C p.Ala894= synonymous_variant 13/21
INSRXM_011527988.3 linkuse as main transcriptc.2718T>C p.Ala906= synonymous_variant 14/22
INSRXM_011527989.4 linkuse as main transcriptc.2682T>C p.Ala894= synonymous_variant 13/21

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
INSRENST00000302850.10 linkuse as main transcriptc.2718T>C p.Ala906= synonymous_variant 14/221 NM_000208.4 A2P06213-1
INSRENST00000341500.9 linkuse as main transcriptc.2682T>C p.Ala894= synonymous_variant 13/211 P3P06213-2

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00824
AC:
1254
AN:
152158
Hom.:
19
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0284
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00386
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.0000882
Gnomad OTH
AF:
0.00430
GnomAD3 exomes
AF:
0.00207
AC:
519
AN:
250846
Hom.:
6
AF XY:
0.00162
AC XY:
220
AN XY:
135632
show subpopulations
Gnomad AFR exome
AF:
0.0283
Gnomad AMR exome
AF:
0.00127
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000980
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000883
Gnomad OTH exome
AF:
0.000490
GnomAD4 exome
AF:
0.000865
AC:
1264
AN:
1461866
Hom.:
18
Cov.:
32
AF XY:
0.000752
AC XY:
547
AN XY:
727234
show subpopulations
Gnomad4 AFR exome
AF:
0.0296
Gnomad4 AMR exome
AF:
0.00165
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000464
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000567
Gnomad4 OTH exome
AF:
0.00215
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00825
AC:
1257
AN:
152276
Hom.:
19
Cov.:
31
AF XY:
0.00810
AC XY:
603
AN XY:
74464
show subpopulations
Gnomad4 AFR
AF:
0.0284
Gnomad4 AMR
AF:
0.00386
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000208
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000882
Gnomad4 OTH
AF:
0.00426
Alfa
AF:
0.00449
Hom.:
6
Bravo
AF:
0.0101
Asia WGS
AF:
0.00115
AC:
4
AN:
3478
EpiCase
AF:
0.000164
EpiControl
AF:
0.00

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Insulin-resistant diabetes mellitus AND acanthosis nigricans Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Rabson-Mendenhall syndrome Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeDec 24, 2023- -
Hyperinsulinism due to INSR deficiency Benign:1
Likely benign, criteria provided, single submitterresearchClinical 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 variant rs2229433 with early onset diabetes mellitus is yet to be ascertained. -
Leprechaunism syndrome Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.87
Cadd
Benign
1.6
Dann
Benign
0.38

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs2229433; hg19: chr19-7132293; API