rs2229435

Variant names:

• chr19-7174608-A-G
• rs2229435
• NM_000208.4:c.1098T>C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000208.4(INSR):​c.1098T>C​(p.Ser366Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0135 in 1,613,494 control chromosomes in the GnomAD database, including 173 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0095 (11 hom., cov: 31)
  • Exomes 𝑓: 0.014 (162 hom.)
• Consequence: INSR NM_000208.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.962

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 19-7174608-A-G is Benign according to our data. Variant chr19-7174608-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 330473.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-7174608-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.962 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00955 (1448/151628) while in subpopulation NFE AF= 0.0157 (1066/67884). AF 95% confidence interval is 0.0149. There are 11 homozygotes in gnomad4. There are 685 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 11 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INSR	NM_000208.4	c.1098T>C	p.Ser366Ser	synonymous_variant	Exon 4 of 22	ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3	c.1098T>C	p.Ser366Ser	synonymous_variant	Exon 4 of 21		NP_001073285.1
INSR	XM_011527988.3	c.1098T>C	p.Ser366Ser	synonymous_variant	Exon 4 of 22		XP_011526290.2
INSR	XM_011527989.4	c.1098T>C	p.Ser366Ser	synonymous_variant	Exon 4 of 21		XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INSR	ENST00000302850.10	c.1098T>C	p.Ser366Ser	synonymous_variant	Exon 4 of 22	1	NM_000208.4	ENSP00000303830.4
INSR	ENST00000341500.9	c.1098T>C	p.Ser366Ser	synonymous_variant	Exon 4 of 21	1		ENSP00000342838.4
INSR	ENST00000598216.1	n.1073T>C		non_coding_transcript_exon_variant	Exon 4 of 10	1

Frequencies

GnomAD3 genomes AF: 0.00956 AC: 1448 AN: 151510 Hom.: 11 Cov.: 31

Gnomad AFR AF: 0.00257

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00738

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00567

Gnomad FIN AF: 0.0111

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0157

Gnomad OTH AF: 0.00624

GnomAD3 exomes AF: 0.00961 AC: 2416 AN: 251406 Hom.: 14 AF XY: 0.00963 AC XY: 1308 AN XY: 135890

Gnomad AFR exome AF: 0.00234

Gnomad AMR exome AF: 0.00408

Gnomad ASJ exome AF: 0.00238

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00562

Gnomad FIN exome AF: 0.0123

Gnomad NFE exome AF: 0.0151

Gnomad OTH exome AF: 0.00945

GnomAD4 exome AF: 0.0139 AC: 20310 AN: 1461866 Hom.: 162 Cov.: 33 AF XY: 0.0136 AC XY: 9895 AN XY: 727236

Gnomad4 AFR exome AF: 0.00203

Gnomad4 AMR exome AF: 0.00409

Gnomad4 ASJ exome AF: 0.00233

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00660

Gnomad4 FIN exome AF: 0.0128

Gnomad4 NFE exome AF: 0.0163

Gnomad4 OTH exome AF: 0.0101

GnomAD4 genome AF: 0.00955 AC: 1448 AN: 151628 Hom.: 11 Cov.: 31 AF XY: 0.00925 AC XY: 685 AN XY: 74064

Gnomad4 AFR AF: 0.00256

Gnomad4 AMR AF: 0.00737

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00547

Gnomad4 FIN AF: 0.0111

Gnomad4 NFE AF: 0.0157

Gnomad4 OTH AF: 0.00618

Alfa AF: 0.0115 Hom.: 7

Bravo AF: 0.00807

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0137

EpiControl AF: 0.0134

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 08, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Apr 20, 2021

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Insulin-resistant diabetes mellitus AND acanthosis nigricans Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 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. -

Hyperinsulinism due to INSR deficiency Benign:1

-

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

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 rs2229435 with early onset diabetes mellitus is yet to be ascertained. -

Leprechaunism syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 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	-0.57
CADD	Benign	6.9
DANN	Benign	0.51
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Other links and lift over

dbSNP: rs2229435; hg19: chr19-7174619; COSMIC: COSV100251262;