rs2229430

chr19-7142832-C-Gchr19-7142832-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000208.4(INSR):c.2526G>C(p.Ala842=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0093 in 1,614,028 control chromosomes in the GnomAD database, including 162 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (48 hom., cov: 32)
  • Exomes 𝑓: 0.0083 (114 hom.)
• Consequence: INSR NM_000208.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.577

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 19-7142832-C-G is Benign according to our data. Variant chr19-7142832-C-G is described in ClinVar as [Benign]. Clinvar id is 330458.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-7142832-C-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.577 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0184 (2803/152306) while in subpopulation AFR AF= 0.0437 (1816/41566). AF 95% confidence interval is 0.042. There are 48 homozygotes in gnomad4. There are 1365 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 47 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INSR	NM_000208.4	c.2526G>C	p.Ala842=	synonymous_variant	12/22	ENST00000302850.10
INSR	NM_001079817.3	c.2490G>C	p.Ala830=	synonymous_variant	11/21
INSR	XM_011527988.3	c.2526G>C	p.Ala842=	synonymous_variant	12/22
INSR	XM_011527989.4	c.2490G>C	p.Ala830=	synonymous_variant	11/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INSR	ENST00000302850.10	c.2526G>C	p.Ala842=	synonymous_variant	12/22	1	NM_000208.4	A2
INSR	ENST00000341500.9	c.2490G>C	p.Ala830=	synonymous_variant	11/21	1		P3
INSR	ENST00000597211.1	n.209G>C		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes AF: 0.0183 AC: 2787 AN: 152188 Hom.: 47 Cov.: 32

Gnomad AFR AF: 0.0434

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00707

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.0416

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.00951

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00664

Gnomad OTH AF: 0.0163

GnomAD3 exomes AF: 0.0113 AC: 2826 AN: 249760 Hom.: 43 AF XY: 0.0100 AC XY: 1359 AN XY: 135292

Gnomad AFR exome AF: 0.0455

Gnomad AMR exome AF: 0.00431

Gnomad ASJ exome AF: 0.0118

Gnomad EAS exome AF: 0.0394

Gnomad SAS exome AF: 0.00203

Gnomad FIN exome AF: 0.0102

Gnomad NFE exome AF: 0.00674

Gnomad OTH exome AF: 0.00981

GnomAD4 exome AF: 0.00835 AC: 12201 AN: 1461722 Hom.: 114 Cov.: 32 AF XY: 0.00794 AC XY: 5777 AN XY: 727184

Gnomad4 AFR exome AF: 0.0426

Gnomad4 AMR exome AF: 0.00465

Gnomad4 ASJ exome AF: 0.0130

Gnomad4 EAS exome AF: 0.0419

Gnomad4 SAS exome AF: 0.00219

Gnomad4 FIN exome AF: 0.0105

Gnomad4 NFE exome AF: 0.00639

Gnomad4 OTH exome AF: 0.0109

GnomAD4 genome AF: 0.0184 AC: 2803 AN: 152306 Hom.: 48 Cov.: 32 AF XY: 0.0183 AC XY: 1365 AN XY: 74490

Gnomad4 AFR AF: 0.0437

Gnomad4 AMR AF: 0.00706

Gnomad4 ASJ AF: 0.0153

Gnomad4 EAS AF: 0.0413

Gnomad4 SAS AF: 0.00414

Gnomad4 FIN AF: 0.00951

Gnomad4 NFE AF: 0.00664

Gnomad4 OTH AF: 0.0161

Alfa AF: 0.00724 Hom.: 6

Bravo AF: 0.0200

Asia WGS AF: 0.0230 AC: 79 AN: 3478

EpiCase AF: 0.00518

EpiControl AF: 0.00510

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Insulin-resistant diabetes mellitus AND acanthosis nigricans Benign:1

Benign, 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 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 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 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 submitter

clinical testing

Invitae

Dec 31, 2023

- -

Leprechaunism syndrome Benign:1

Benign, 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 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	-0.33
Cadd	Benign	6.4
Dann	Benign	0.73

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: rs2229430; hg19: chr19-7142843; COSMIC: COSV57164971;