19-7166365-C-T

Position:

• chr19-7166365-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000208.4(INSR):​c.1650G>A​(p.Ala550Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.244 in 1,613,598 control chromosomes in the GnomAD database, including 48,864 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4228 hom., cov: 31)
  • Exomes 𝑓: 0.24 (44636 hom.)
• Consequence: INSR NM_000208.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -4.84

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 19-7166365-C-T is Benign according to our data. Variant chr19-7166365-C-T is described in ClinVar as [Benign]. Clinvar id is 198697.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-7166365-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-4.84 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.261 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INSR	NM_000208.4	c.1650G>A	p.Ala550Ala	synonymous_variant	8/22	ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3	c.1650G>A	p.Ala550Ala	synonymous_variant	8/21		NP_001073285.1
INSR	XM_011527988.3	c.1650G>A	p.Ala550Ala	synonymous_variant	8/22		XP_011526290.2
INSR	XM_011527989.4	c.1650G>A	p.Ala550Ala	synonymous_variant	8/21		XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INSR	ENST00000302850.10	c.1650G>A	p.Ala550Ala	synonymous_variant	8/22	1	NM_000208.4	ENSP00000303830.4
INSR	ENST00000341500.9	c.1650G>A	p.Ala550Ala	synonymous_variant	8/21	1		ENSP00000342838.4
INSR	ENST00000598216.1	n.1625G>A		non_coding_transcript_exon_variant	8/10	1
INSR	ENST00000600492.1	c.51G>A	p.Ala17Ala	synonymous_variant	2/4	5		ENSP00000473170.1

Frequencies

GnomAD3 genomes AF: 0.233 AC: 35453 AN: 151892 Hom.: 4223 Cov.: 31

Gnomad AFR AF: 0.184

Gnomad AMI AF: 0.160

Gnomad AMR AF: 0.238

Gnomad ASJ AF: 0.311

Gnomad EAS AF: 0.256

Gnomad SAS AF: 0.273

Gnomad FIN AF: 0.332

Gnomad MID AF: 0.240

Gnomad NFE AF: 0.238

Gnomad OTH AF: 0.262

GnomAD3 exomes AF: 0.256 AC: 64344 AN: 250902 Hom.: 8303 AF XY: 0.258 AC XY: 34977 AN XY: 135648

Gnomad AFR exome AF: 0.186

Gnomad AMR exome AF: 0.258

Gnomad ASJ exome AF: 0.322

Gnomad EAS exome AF: 0.250

Gnomad SAS exome AF: 0.261

Gnomad FIN exome AF: 0.321

Gnomad NFE exome AF: 0.248

Gnomad OTH exome AF: 0.265

GnomAD4 exome AF: 0.245 AC: 357816 AN: 1461588 Hom.: 44636 Cov.: 38 AF XY: 0.246 AC XY: 178559 AN XY: 727078

Gnomad4 AFR exome AF: 0.180

Gnomad4 AMR exome AF: 0.254

Gnomad4 ASJ exome AF: 0.314

Gnomad4 EAS exome AF: 0.231

Gnomad4 SAS exome AF: 0.266

Gnomad4 FIN exome AF: 0.316

Gnomad4 NFE exome AF: 0.240

Gnomad4 OTH exome AF: 0.249

GnomAD4 genome AF: 0.233 AC: 35467 AN: 152010 Hom.: 4228 Cov.: 31 AF XY: 0.237 AC XY: 17615 AN XY: 74272

Gnomad4 AFR AF: 0.184

Gnomad4 AMR AF: 0.238

Gnomad4 ASJ AF: 0.311

Gnomad4 EAS AF: 0.256

Gnomad4 SAS AF: 0.273

Gnomad4 FIN AF: 0.332

Gnomad4 NFE AF: 0.239

Gnomad4 OTH AF: 0.262

Alfa AF: 0.236 Hom.: 5779

Bravo AF: 0.223

Asia WGS AF: 0.272 AC: 943 AN: 3478

EpiCase AF: 0.243

EpiControl AF: 0.252

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 04, 2021	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	This variant is associated with the following publications: (PMID: 10933564) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Rabson-Mendenhall syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 15, 2018	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Leprechaunism syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jan 28, 2015

- -

Insulin-resistant diabetes mellitus AND acanthosis nigricans Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.046
DANN	Benign	0.43
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: rs2059806; hg19: chr19-7166376; COSMIC: COSV57156775;