7-76303820-A-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM1BS2

The NM_001540.5(HSPB1):c.383A>G(p.Gln128Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000547 in 1,573,300 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Q128Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000034 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000057 ( 0 hom. )

Consequence

HSPB1
NM_001540.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1B:1

Conservation

PhyloP100: 5.21

Publications

5 publications found

Variant links:

Genes affected

HSPB1 (HGNC:5246): (heat shock protein family B (small) member 1) This gene encodes a member of the small heat shock protein (HSP20) family of proteins. In response to environmental stress, the encoded protein translocates from the cytoplasm to the nucleus and functions as a molecular chaperone that promotes the correct folding of other proteins. This protein plays an important role in the differentiation of a wide variety of cell types. Expression of this gene is correlated with poor clinical outcome in multiple human cancers, and the encoded protein may promote cancer cell proliferation and metastasis, while protecting cancer cells from apoptosis. Mutations in this gene have been identified in human patients with Charcot-Marie-Tooth disease and distal hereditary motor neuropathy. [provided by RefSeq, Aug 2017]

HSPB1 Gene-Disease associations (from GenCC):

Charcot-Marie-Tooth disease axonal type 2F
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Illumina, Labcorp Genetics (formerly Invitae)
neuronopathy, distal hereditary motor, type 2B
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
distal hereditary motor neuropathy type 2
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

HSPB1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM1

In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 18 uncertain in NM_001540.5

BS2

High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPB1	NM_001540.5 link	c.383A>G	p.Gln128Arg	missense_variant	Exon 2 of 3	ENST00000248553.7	NP_001531.1	P04792V9HW43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSPB1	ENST00000248553.7 link	c.383A>G	p.Gln128Arg	missense_variant	Exon 2 of 3	1	NM_001540.5	ENSP00000248553.6		P04792

Frequencies

GnomAD3 genomes

AF:

0.0000342

AC:

AN:

146408

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000753

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000482

AC:

AN:

248938

AF XY:

0.0000443

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000714

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000568

AC:

AN:

1426770

Hom.:

Cov.:

AF XY:

0.0000578

AC XY:

AN XY:

709470

show subpopulations

African (AFR)

AF:

0.0000310

AC:

AN:

32310

American (AMR)

AF:

0.0000229

AC:

AN:

43608

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24680

East Asian (EAS)

AF:

0.00

AC:

AN:

37272

South Asian (SAS)

AF:

0.000117

AC:

AN:

85814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4050

European-Non Finnish (NFE)

AF:

0.0000614

AC:

AN:

1090816

Other (OTH)

AF:

0.0000346

AC:

AN:

57804

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000341

AC:

AN:

146530

Hom.:

Cov.:

AF XY:

0.0000560

AC XY:

AN XY:

71442

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40224

American (AMR)

AF:

0.00

AC:

AN:

14810

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3410

East Asian (EAS)

AF:

0.00

AC:

AN:

4522

South Asian (SAS)

AF:

0.00

AC:

AN:

4334

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9572

Middle Eastern (MID)

AF:

0.00

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.0000753

AC:

AN:

66440

Other (OTH)

AF:

0.00

AC:

AN:

2048

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.565

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000508

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000660

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease axonal type 2F

Pathogenic:1

Jun 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 128 of the HSPB1 protein (p.Gln128Arg). This variant is present in population databases (rs558882005, gnomAD 0.01%). This missense change has been observed in individuals with autosomal dominant HSPB1-related conditions (PMID: 28144995, 31069529; Invitae). ClinVar contains an entry for this variant (Variation ID: 360738). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt HSPB1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects HSPB1 function (PMID: 28144995). For these reasons, this variant has been classified as Pathogenic. -

Neuronopathy, distal hereditary motor, type 2B

Pathogenic:1

Feb 02, 2017

Biochimie - Maladies Neurologiques Hereditaires, Hospices Civils de Lyon

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Charcot-Marie-Tooth disease

Uncertain:1

Molecular Genetics Laboratory, London Health Sciences Centre

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Dec 21, 2021

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.068

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.86

M_CAP

Pathogenic

0.59

MetaRNN

Uncertain

0.57

MetaSVM

Uncertain

0.66

MutationAssessor

Benign

1.8

PhyloP100

5.2

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-2.7

REVEL

Uncertain

0.59

Sift

Uncertain

0.012

Sift4G

Uncertain

0.0090

Polyphen

0.47

Vest4

0.40

MVP

0.96

MPC

0.68

ClinPred

0.70

GERP RS

4.4

PromoterAI

-0.033

Neutral

(source)

Varity_R

0.83

gMVP

0.48

Mutation Taster

=30/70

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over