rs142654992

Variant names:

• chr19-7143063-G-A
• rs142654992
• NM_000208.4:c.2295C>T
• INSR p.Gly765Gly

Your query was ambiguous. Multiple possible variants found:

• chr19-7143063-G-A
• chr19-7143063-G-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_000208.4(INSR):​c.2295C>T​(p.Gly765Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000792 in 1,614,158 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00064 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00081 (2 hom.)
• Consequence: INSR NM_000208.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:8
• Conservation: PhyloP100: -1.49
• Publications: 2 publications found

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: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
• Donohue syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• hyperinsulinism due to INSR deficiency

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• Rabson-Mendenhall syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 19-7143063-G-A is Benign according to our data. Variant chr19-7143063-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 330462.
• BP7: Synonymous conserved (PhyloP=-1.49 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000644 (98/152276) while in subpopulation SAS AF = 0.0029 (14/4824). AF 95% confidence interval is 0.00175. There are 0 homozygotes in GnomAd4. There are 48 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000208.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INSR	NM_000208.4	MANE Select	c.2295C>T	p.Gly765Gly	synonymous	Exon 12 of 22	NP_000199.2	P06213-1
	INSR	NM_001079817.3		c.2259C>T	p.Gly753Gly	synonymous	Exon 11 of 21	NP_001073285.1	P06213-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INSR	ENST00000302850.10	TSL:1 MANE Select	c.2295C>T	p.Gly765Gly	synonymous	Exon 12 of 22	ENSP00000303830.4	P06213-1
	INSR	ENST00000341500.9	TSL:1	c.2259C>T	p.Gly753Gly	synonymous	Exon 11 of 21	ENSP00000342838.4	P06213-2
	INSR	ENST00000904791.1		c.2295C>T	p.Gly765Gly	synonymous	Exon 12 of 22	ENSP00000574850.1

Frequencies

GnomAD3 genomes AF: 0.000644 AC: 98 AN: 152158 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000941

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000792 AC: 199 AN: 251140 AF XY: 0.00102

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000987

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000807 AC: 1180 AN: 1461882 Hom.: 2 Cov.: 32 AF XY: 0.000872 AC XY: 634 AN XY: 727246

African (AFR) AF: 0.000149 AC: 5 AN: 33480

American (AMR) AF: 0.000179 AC: 8 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000383 AC: 10 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00284 AC: 245 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00225 AC: 13 AN: 5768

European-Non Finnish (NFE) AF: 0.000768 AC: 854 AN: 1112004

Other (OTH) AF: 0.000745 AC: 45 AN: 60396

GnomAD4 genome AF: 0.000644 AC: 98 AN: 152276 Hom.: 0 Cov.: 32 AF XY: 0.000645 AC XY: 48 AN XY: 74450

African (AFR) AF: 0.000217 AC: 9 AN: 41556

American (AMR) AF: 0.000523 AC: 8 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000941 AC: 64 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000625 Hom.: 0

Bravo AF: 0.000771

EpiCase AF: 0.000763

EpiControl AF: 0.00113

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	1	Hyperinsulinism due to INSR deficiency (1)
-	-	1	INSR-related disorder (1)
-	1	-	Insulin-resistant diabetes mellitus AND acanthosis nigricans (1)
-	1	-	Leprechaunism syndrome (1)
-	1	-	Rabson-Mendenhall syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.051
DANN	Benign	0.46
PhyloP100		-1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs142654992;

hg19: chr19-7143074;