NM_003299.3:c.2297C>G

Variant names:

• chr12-103947345-C-G
• NM_003299.3:c.2297C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003299.3(HSP90B1):​c.2297C>G​(p.Thr766Arg) 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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: HSP90B1 NM_003299.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.30
• Publications: 0 publications found

Genes affected

HSP90B1 (HGNC:12028): (heat shock protein 90 beta family member 1) This gene encodes a member of a family of adenosine triphosphate(ATP)-metabolizing molecular chaperones with roles in stabilizing and folding other proteins. The encoded protein is localized to melanosomes and the endoplasmic reticulum. Expression of this protein is associated with a variety of pathogenic states, including tumor formation. There is a microRNA gene located within the 5' exon of this gene. There are pseudogenes for this gene on chromosomes 1 and 15. [provided by RefSeq, Aug 2012]

UQCC6 (HGNC:34450): (ubiquinol-cytochrome c reductase complex assembly factor 6) Involved in mitochondrial respiratory chain complex III assembly. Located in mitochondrial inner membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.071050406).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003299.3. 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
	HSP90B1	NM_003299.3	MANE Select	c.2297C>G	p.Thr766Arg	missense	Exon 17 of 18	NP_003290.1	P14625

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSP90B1	ENST00000299767.10	TSL:1 MANE Select	c.2297C>G	p.Thr766Arg	missense	Exon 17 of 18	ENSP00000299767.4	P14625
	HSP90B1	ENST00000614327.2	TSL:1	c.2141C>G	p.Thr714Arg	missense	Exon 16 of 17	ENSP00000477660.2	A0A087WT78
	HSP90B1	ENST00000681861.1		c.2297C>G	p.Thr766Arg	missense	Exon 17 of 17	ENSP00000506419.1	A0A7P0TAT8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	19
DANN	Benign	0.91
DEOGEN2	Benign	0.076	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.071	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.3
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	0.070	N
REVEL	Benign	0.067
Sift	Benign	0.47	T
Sift4G	Benign	0.49	T
Polyphen		0.067	B
Vest4		0.28
MutPred		0.31		Loss of phosphorylation at T766 (P = 9e-04)
MVP		0.44
MPC		0.48
ClinPred		0.17	T
GERP RS		3.9
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.1
Varity_R		0.17
gMVP		0.076
Mutation Taster		=95/5	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

hg19: chr12-104341123;