rs747381453

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM1PP3

The NM_014365.3(HSPB8):c.65G>A(p.Arg22Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,932 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

HSPB8
NM_014365.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.15

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM1

In a chain Heat shock protein beta-8 (size 195) in uniprot entity HSPB8_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_014365.3

PP3

MetaRNN computational evidence supports a deleterious effect, 0.765

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPB8	NM_014365.3 link	c.65G>A	p.Arg22Gln	missense_variant	Exon 1 of 3	ENST00000281938.7	NP_055180.1	Q9UJY1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HSPB8	ENST00000281938.7 link	c.65G>A	p.Arg22Gln	missense_variant	Exon 1 of 3	1	NM_014365.3	ENSP00000281938.3	Q9UJY1
HSPB8	ENST00000674542.1 link	c.65G>A	p.Arg22Gln	missense_variant	Exon 1 of 2			ENSP00000502352.1	A0A6Q8PGM6
HSPB8	ENST00000676244.1 link	n.73+5379G>A		intron_variant	Intron 1 of 2
HSPB8	ENST00000541798.1 link	c.-215G>A		upstream_gene_variant		3		ENSP00000441541.1	H0YG30

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

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:

0.00000795

AC:

AN:

251428

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461840

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152092

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74290

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease axonal type 2L

Uncertain:1

Nov 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 22 of the HSPB8 protein (p.Arg22Gln). This variant is present in population databases (rs747381453, gnomAD 0.002%). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 32376792). ClinVar contains an entry for this variant (Variation ID: 581856). 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 disruptive. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.31

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.88

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.77

MetaSVM

Uncertain

0.47

MutationAssessor

Uncertain

2.5

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-2.0

REVEL

Uncertain

0.59

Sift

Benign

0.040

Sift4G

Benign

0.073

Polyphen

1.0

Vest4

0.63

MutPred

0.34

Loss of methylation at R22 (P = 0.0075);

MVP

0.97

MPC

0.73

ClinPred

0.93

GERP RS

4.4

Varity_R

0.44

gMVP

0.59

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over