chr19-7166377-G-C

Variant names:

• chr19-7166377-G-C
• rs2229429
• NM_000208.4:c.1638C>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.1638C>G​(p.Asp546Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D546D) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: INSR NM_000208.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.109
• Publications: 20 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, G2P
• Donohue syndrome

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

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

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

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=0.31058127).

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.1638C>G	p.Asp546Glu	missense	Exon 8 of 22	NP_000199.2	P06213-1
	INSR	NM_001079817.3		c.1638C>G	p.Asp546Glu	missense	Exon 8 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.1638C>G	p.Asp546Glu	missense	Exon 8 of 22	ENSP00000303830.4	P06213-1
	INSR	ENST00000341500.9	TSL:1	c.1638C>G	p.Asp546Glu	missense	Exon 8 of 21	ENSP00000342838.4	P06213-2
	INSR	ENST00000598216.1	TSL:1	n.1613C>G		non_coding_transcript_exon	Exon 8 of 10

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Uncertain	0.058	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	11
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.74	D
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.69	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		-0.11
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.30
Sift	Benign	0.059	T
Sift4G	Benign	0.11	T
Polyphen		0.12	B
Vest4		0.28
MutPred		0.38		Gain of loop (P = 0.1069)
MVP		0.69
MPC		1.8
ClinPred		0.94	D
GERP RS		-4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.33
gMVP		0.92
Mutation Taster		=42/58	disease causing

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: rs2229429; hg19: chr19-7166388;