19-7163054-G-A

Position:

• chr19-7163054-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000208.4(INSR):​c.2007C>T​(p.Phe669=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0714 in 1,613,450 control chromosomes in the GnomAD database, including 4,490 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.081 (573 hom., cov: 30)
  • Exomes 𝑓: 0.070 (3917 hom.)
• Consequence: INSR NM_000208.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0430

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=-0.43).
• BP6: Variant 19-7163054-G-A is Benign according to our data. Variant chr19-7163054-G-A is described in ClinVar as [Benign]. Clinvar id is 330466.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.043 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.11 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INSR	NM_000208.4	c.2007C>T	p.Phe669=	synonymous_variant	9/22	ENST00000302850.10
INSR	NM_001079817.3	c.2007C>T	p.Phe669=	synonymous_variant	9/21
INSR	XM_011527988.3	c.2007C>T	p.Phe669=	synonymous_variant	9/22
INSR	XM_011527989.4	c.2007C>T	p.Phe669=	synonymous_variant	9/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INSR	ENST00000302850.10	c.2007C>T	p.Phe669=	synonymous_variant	9/22	1	NM_000208.4	A2
INSR	ENST00000341500.9	c.2007C>T	p.Phe669=	synonymous_variant	9/21	1		P3
INSR	ENST00000598216.1	n.1982C>T		non_coding_transcript_exon_variant	9/10	1
INSR	ENST00000600492.1	c.408C>T	p.Phe136=	synonymous_variant	3/4	5

Frequencies

GnomAD3 genomes AF: 0.0807 AC: 12252 AN: 151834 Hom.: 574 Cov.: 30

Gnomad AFR AF: 0.113

Gnomad AMI AF: 0.211

Gnomad AMR AF: 0.0526

Gnomad ASJ AF: 0.0605

Gnomad EAS AF: 0.0257

Gnomad SAS AF: 0.0425

Gnomad FIN AF: 0.0682

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0764

Gnomad OTH AF: 0.0644

GnomAD3 exomes AF: 0.0643 AC: 16169 AN: 251466 Hom.: 629 AF XY: 0.0638 AC XY: 8673 AN XY: 135908

Gnomad AFR exome AF: 0.113

Gnomad AMR exome AF: 0.0412

Gnomad ASJ exome AF: 0.0646

Gnomad EAS exome AF: 0.0261

Gnomad SAS exome AF: 0.0486

Gnomad FIN exome AF: 0.0650

Gnomad NFE exome AF: 0.0744

Gnomad OTH exome AF: 0.0682

GnomAD4 exome AF: 0.0704 AC: 102916 AN: 1461498 Hom.: 3917 Cov.: 32 AF XY: 0.0697 AC XY: 50654 AN XY: 727054

Gnomad4 AFR exome AF: 0.111

Gnomad4 AMR exome AF: 0.0440

Gnomad4 ASJ exome AF: 0.0660

Gnomad4 EAS exome AF: 0.0218

Gnomad4 SAS exome AF: 0.0468

Gnomad4 FIN exome AF: 0.0635

Gnomad4 NFE exome AF: 0.0743

Gnomad4 OTH exome AF: 0.0721

GnomAD4 genome AF: 0.0807 AC: 12260 AN: 151952 Hom.: 573 Cov.: 30 AF XY: 0.0786 AC XY: 5837 AN XY: 74252

Gnomad4 AFR AF: 0.113

Gnomad4 AMR AF: 0.0525

Gnomad4 ASJ AF: 0.0605

Gnomad4 EAS AF: 0.0256

Gnomad4 SAS AF: 0.0429

Gnomad4 FIN AF: 0.0682

Gnomad4 NFE AF: 0.0764

Gnomad4 OTH AF: 0.0642

Alfa AF: 0.0764 Hom.: 412

Bravo AF: 0.0815

Asia WGS AF: 0.0450 AC: 155 AN: 3478

EpiCase AF: 0.0738

EpiControl AF: 0.0767

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 24, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

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. -

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	-0.43
CADD	Benign	0.32
DANN	Benign	0.83

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: rs2962; hg19: chr19-7163065; COSMIC: COSV57158641;