12-119179578-C-T

Variant names:

• chr12-119179578-C-T
• rs35909818
• NM_014365.3:c.266C>T

Variant summary

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

The NM_014365.3(HSPB8):​c.266C>T​(p.Pro89Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P89Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HSPB8 NM_014365.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.26
• Publications: 2 publications found

Genes affected

HSPB8 (HGNC:30171): (heat shock protein family B (small) member 8) The protein encoded by this gene belongs to the superfamily of small heat-shock proteins containing a conservative alpha-crystallin domain at the C-terminal part of the molecule. The expression of this gene in induced by estrogen in estrogen receptor-positive breast cancer cells, and this protein also functions as a chaperone in association with Bag3, a stimulator of macroautophagy. Thus, this gene appears to be involved in regulation of cell proliferation, apoptosis, and carcinogenesis, and mutations in this gene have been associated with different neuromuscular diseases, including Charcot-Marie-Tooth disease. [provided by RefSeq, Jul 2008]

HSPB8 Gene-Disease associations (from GenCC):

• neuronopathy, distal hereditary motor, autosomal dominant

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Charcot-Marie-Tooth disease axonal type 2L

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• neuronopathy, distal hereditary motor, type 2A

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• autosomal dominant distal axonal motor neuropathy-myofibrillar myopathy syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• distal hereditary motor neuropathy type 2

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

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=0.18931785).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014365.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPB8	NM_014365.3	MANE Select	c.266C>T	p.Pro89Leu	missense	Exon 1 of 3	NP_055180.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPB8	ENST00000281938.7	TSL:1 MANE Select	c.266C>T	p.Pro89Leu	missense	Exon 1 of 3	ENSP00000281938.3
	HSPB8	ENST00000674542.1		c.266C>T	p.Pro89Leu	missense	Exon 1 of 2	ENSP00000502352.1
	HSPB8	ENST00000676244.1		n.73+5580C>T		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459880 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726034

African (AFR) AF: 0.00 AC: 0 AN: 33366

American (AMR) AF: 0.00 AC: 0 AN: 44514

Ashkenazi Jewish (ASJ) AF: 0.0000384 AC: 1 AN: 26010

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.00 AC: 0 AN: 86152

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53268

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110870

Other (OTH) AF: 0.00 AC: 0 AN: 60276

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-Marie-Tooth disease axonal type 2L Uncertain:1

Mar 05, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant has not been reported in the literature in individuals with HSPB8-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with leucine at codon 89 of the HSPB8 protein (p.Pro89Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Uncertain	0.029	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	22
DANN	Benign	0.87
DEOGEN2	Benign	0.072	T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.058
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	1.6	L
PhyloP100		2.3
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	0.89	N
REVEL	Benign	0.27
Sift	Benign	0.30	T
Sift4G	Benign	0.47	T
Polyphen		0.056	B
Vest4		0.28
MutPred		0.39		Gain of catalytic residue at P89 (P = 0.0011)
MVP		0.94
MPC		0.24
ClinPred		0.72	D
GERP RS		4.4
PromoterAI		-0.034	Neutral
Varity_R		0.16
gMVP		0.47
Mutation Taster		=78/22	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: rs35909818; hg19: chr12-119617383;