rs551013013

chr12-119193837-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014365.3(HSPB8):c.570C>A(p.Ser190Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,290 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: HSPB8 NM_014365.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.37

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.061978847).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSPB8	NM_014365.3	c.570C>A	p.Ser190Arg	missense_variant	3/3	ENST00000281938.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSPB8	ENST00000281938.7	c.570C>A	p.Ser190Arg	missense_variant	3/3	1	NM_014365.3	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251494 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135922

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152290 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74464

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 16, 2019

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 26, 2023

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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 582846). This variant has not been reported in the literature in individuals affected with HSPB8-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 190 of the HSPB8 protein (p.Ser190Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.039	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.038
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.062	T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	0.98	D
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.68	N
REVEL	Benign	0.13
Sift	Uncertain	0.024	D
Sift4G	Benign	0.067	T
Polyphen		0.010	B
Vest4		0.11
MutPred		0.27		Gain of catalytic residue at E192 (P = 0.0363);
MVP		0.93
MPC		0.27
ClinPred		0.59	D
GERP RS		4.3
Varity_R		0.12
gMVP		0.16

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

LitVar

Other links and lift over

dbSNP: rs551013013; hg19: chr12-119631642;