GeneBe

NM_000208.4:c.687C>G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_StrongBP7

The NM_000208.4(INSR):​c.687C>G​(p.Thr229Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. T229T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 30)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

INSR
NM_000208.4 synonymous

Scores

2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.85

Publications

1 publications found
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]
INSR Gene-Disease associations (from GenCC):
  • insulin-resistance syndrome type A
    Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, G2P
  • Donohue syndrome
    Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P
  • hyperinsulinism due to INSR deficiency
    Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, Ambry Genetics
  • Rabson-Mendenhall syndrome
    Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.88).
BP7
Synonymous conserved (PhyloP=-1.85 with no splicing effect.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
INSRNM_000208.4 linkc.687C>G p.Thr229Thr synonymous_variant Exon 3 of 22 ENST00000302850.10 NP_000199.2 P06213-1
INSRNM_001079817.3 linkc.687C>G p.Thr229Thr synonymous_variant Exon 3 of 21 NP_001073285.1 P06213-2
INSRXM_011527988.3 linkc.687C>G p.Thr229Thr synonymous_variant Exon 3 of 22 XP_011526290.2
INSRXM_011527989.4 linkc.687C>G p.Thr229Thr synonymous_variant Exon 3 of 21 XP_011526291.2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
INSRENST00000302850.10 linkc.687C>G p.Thr229Thr synonymous_variant Exon 3 of 22 1 NM_000208.4 ENSP00000303830.4 P06213-1
INSRENST00000341500.9 linkc.687C>G p.Thr229Thr synonymous_variant Exon 3 of 21 1 ENSP00000342838.4 P06213-2
INSRENST00000598216.1 linkn.662C>G non_coding_transcript_exon_variant Exon 3 of 10 1

Frequencies

GnomAD3 genomes
Cov.:
30
GnomAD2 exomes
AF:
0.00000405
AC:
1
AN:
246626
AF XY:
0.00
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461020
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
726810
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33460
American (AMR)
AF:
0.00
AC:
0
AN:
44710
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26118
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39698
South Asian (SAS)
AF:
0.0000464
AC:
4
AN:
86222
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
52988
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5584
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1111904
Other (OTH)
AF:
0.00
AC:
0
AN:
60336
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.538
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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
Cov.:
30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.88
CADD
Benign
0.049
DANN
Benign
0.43
PhyloP100
-1.8

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

Other links and lift over

dbSNP: rs150568177; hg19: chr19-7184614; API