12-103947345-C-G

Position:

• chr12-103947345-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 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. 14/21 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

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]

HSP90B1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSP90B1	NM_003299.3	c.2297C>G	p.Thr766Arg	missense_variant	17/18	ENST00000299767.10	NP_003290.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSP90B1	ENST00000299767.10	c.2297C>G	p.Thr766Arg	missense_variant	17/18	1	NM_003299.3	ENSP00000299767.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 25, 2024

The c.2297C>G (p.T766R) alteration is located in exon 17 (coding exon 17) of the HSP90B1 gene. This alteration results from a C to G substitution at nucleotide position 2297, causing the threonine (T) at amino acid position 766 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

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
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

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-104341123;