rs755233365

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 3P and 4B. PM1PP3BS2

The NM_001540.5(HSPB1):c.369G>C(p.Lys123Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000371 in 1,456,990 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K123M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000037 ( 0 hom. )

Consequence

HSPB1
NM_001540.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -0.102

Publications

0 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 -1 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_001540.5

PP3

MetaRNN computational evidence supports a deleterious effect, 0.834

BS2

High AC in GnomAdExome4 at 54 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPB1	NM_001540.5 link	c.369G>C	p.Lys123Asn	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.369G>C	p.Lys123Asn	missense_variant	Exon 2 of 3	1	NM_001540.5	ENSP00000248553.6		P04792

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000201

AC:

AN:

248876

AF XY:

0.0000296

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:

0.0000447

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000371

AC:

AN:

1456990

Hom.:

Cov.:

AF XY:

0.0000359

AC XY:

AN XY:

724804

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33346

American (AMR)

AF:

0.00

AC:

AN:

44666

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26074

East Asian (EAS)

AF:

0.00

AC:

AN:

39556

South Asian (SAS)

AF:

0.00

AC:

AN:

86152

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52102

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4182

European-Non Finnish (NFE)

AF:

0.0000486

AC:

AN:

1110858

Other (OTH)

AF:

0.00

AC:

AN:

60054

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

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

Cov.:

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease axonal type 2F

Uncertain:1

Oct 17, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. 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. ClinVar contains an entry for this variant (Variation ID: 533812). This variant has not been reported in the literature in individuals affected with HSPB1-related conditions. This variant is present in population databases (rs755233365, gnomAD 0.005%). This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 123 of the HSPB1 protein (p.Lys123Asn). -

not provided

Uncertain:1

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

HSPB1: PP3 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Benign

-0.0076

BayesDel_noAF

Benign

-0.12

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

Eigen

Uncertain

0.22

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.91

M_CAP

Pathogenic

0.51

MetaRNN

Pathogenic

0.83

MetaSVM

Uncertain

0.53

MutationAssessor

Uncertain

2.6

PhyloP100

-0.10

PrimateAI

Pathogenic

0.87

PROVEAN

Uncertain

-4.1

REVEL

Pathogenic

0.69

Sift

Benign

0.035

Sift4G

Benign

0.065

Polyphen

0.94

Vest4

0.55

MutPred

0.62

Loss of ubiquitination at K123 (P = 0.0116);

MVP

0.96

MPC

1.6

ClinPred

0.97

GERP RS

0.43

PromoterAI

-0.027

Neutral

(source)

Varity_R

0.84

gMVP

0.77

Mutation Taster

=30/70

disease causing

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over