rs387906539

Variant names:

• chr19-7184592-A-C
• rs387906539
• NM_000208.4:c.698T>G

Your query was ambiguous. Multiple possible variants found:

• chr19-7184592-A-C
• chr19-7184592-A-G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_000208.4(INSR):​c.698T>G​(p.Leu233Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,506 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: INSR NM_000208.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 3.48
• Publications: 0 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):

• Donohue syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, G2P
• insulin-resistance syndrome type A

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae), G2P
• 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the INSR gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 29 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Gene score misZ: 3.8314 (above the threshold of 3.09). Trascript score misZ: 5.4593 (above the threshold of 3.09). GenCC associations: The gene is linked to Rabson-Mendenhall syndrome, hyperinsulinism due to INSR deficiency, Donohue syndrome, insulin-resistance syndrome type A.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3278795).

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.698T>G	p.Leu233Arg	missense	Exon 3 of 22	NP_000199.2
	INSR	NM_001079817.3		c.698T>G	p.Leu233Arg	missense	Exon 3 of 21	NP_001073285.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INSR	ENST00000302850.10	TSL:1 MANE Select	c.698T>G	p.Leu233Arg	missense	Exon 3 of 22	ENSP00000303830.4
	INSR	ENST00000341500.9	TSL:1	c.698T>G	p.Leu233Arg	missense	Exon 3 of 21	ENSP00000342838.4
	INSR	ENST00000598216.1	TSL:1	n.673T>G		non_coding_transcript_exon	Exon 3 of 10

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461506 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727062

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53140

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111992

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome Cov.: 30

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Uncertain	0.023	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Uncertain	0.47	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	-0.60	N
PhyloP100		3.5
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	1.4	N
REVEL	Uncertain	0.31
Sift	Benign	0.34	T
Sift4G	Benign	0.34	T
Polyphen		0.0020	B
Vest4		0.25
MutPred		0.58		Gain of disorder (P = 0.0151)
MVP		0.77
MPC		1.2
ClinPred		0.58	D
GERP RS		4.0
Varity_R		0.37
gMVP		0.77
Mutation Taster		=89/11	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

Other links and lift over

dbSNP: rs387906539; hg19: chr19-7184603;