dbSNP rs1122326: HSPB9:p.Gln2Pro (chr17-42122855-A-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_033194.3(HSPB9):c.5A>C(p.Gln2Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.241 in 1,604,988 control chromosomes in the GnomAD database, including 52,820 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q2H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.33 ( 10566 hom., cov: 33)

Exomes 𝑓: 0.23 ( 42254 hom. )

Consequence

HSPB9
NM_033194.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.757

Publications

36 publications found

Variant links:

Genes affected

HSPB9 (HGNC:30589): (heat shock protein family B (small) member 9) Located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

HSPB9 links:

ENSG00000267261 (HGNC:):

ENSG00000267261 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=3.1186435E-5).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.596 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPB9	NM_033194.3 link	c.5A>C	p.Gln2Pro	missense_variant	Exon 1 of 1	ENST00000565659.2	NP_149971.1	Q9BQS6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HSPB9	ENST00000565659.2 link	c.5A>C	p.Gln2Pro	missense_variant	Exon 1 of 1	6	NM_033194.3	ENSP00000458018.1	Q9BQS6
ENSG00000267261	ENST00000592574.1 link	c.442-2026T>G		intron_variant	Intron 4 of 7	5		ENSP00000468367.1	K7ERQ8
ENSG00000267261	ENST00000585562.5 link	n.*158-2026T>G		intron_variant	Intron 1 of 4	3		ENSP00000464838.1	K7EIP6
ENSG00000267261	ENST00000592248.5 link	n.442-2485T>G		intron_variant	Intron 3 of 4	3		ENSP00000468275.1	K7ERI8

Frequencies

GnomAD3 genomes

AF:

0.329

AC:

50104

AN:

152112

Hom.:

10552

Cov.:

show subpopulations

Gnomad AFR

AF:

0.603

Gnomad AMI

AF:

0.393

Gnomad AMR

AF:

0.225

Gnomad ASJ

AF:

0.185

Gnomad EAS

AF:

0.151

Gnomad SAS

AF:

0.230

Gnomad FIN

AF:

0.243

Gnomad MID

AF:

0.282

Gnomad NFE

AF:

0.228

Gnomad OTH

AF:

0.296

GnomAD2 exomes

AF:

0.238

AC:

59310

AN:

249082

AF XY:

0.234

show subpopulations

Gnomad AFR exome

AF:

0.611

Gnomad AMR exome

AF:

0.159

Gnomad ASJ exome

AF:

0.194

Gnomad EAS exome

AF:

0.149

Gnomad FIN exome

AF:

0.232

Gnomad NFE exome

AF:

0.232

Gnomad OTH exome

AF:

0.222

GnomAD4 exome

AF:

0.232

AC:

337360

AN:

1452758

Hom.:

42254

Cov.:

AF XY:

0.230

AC XY:

166098

AN XY:

720968

show subpopulations

African (AFR)

AF:

0.622

AC:

20709

AN:

33306

American (AMR)

AF:

0.167

AC:

7429

AN:

44518

Ashkenazi Jewish (ASJ)

AF:

0.191

AC:

4963

AN:

25938

East Asian (EAS)

AF:

0.157

AC:

6185

AN:

39458

South Asian (SAS)

AF:

0.221

AC:

19037

AN:

86006

European-Finnish (FIN)

AF:

0.234

AC:

12367

AN:

52798

Middle Eastern (MID)

AF:

0.242

AC:

1253

AN:

5170

European-Non Finnish (NFE)

AF:

0.227

AC:

250621

AN:

1105662

Other (OTH)

AF:

0.247

AC:

14796

AN:

59902

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

14960

29920

44880

59840

74800

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8756

17512

26268

35024

43780

<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:

0.329

AC:

50159

AN:

152230

Hom.:

10566

Cov.:

AF XY:

0.326

AC XY:

24284

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.603

AC:

25032

AN:

41546

American (AMR)

AF:

0.225

AC:

3438

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.185

AC:

642

AN:

3470

East Asian (EAS)

AF:

0.151

AC:

780

AN:

5164

South Asian (SAS)

AF:

0.229

AC:

1104

AN:

4826

European-Finnish (FIN)

AF:

0.243

AC:

2575

AN:

10608

Middle Eastern (MID)

AF:

0.282

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.228

AC:

15523

AN:

67992

Other (OTH)

AF:

0.295

AC:

625

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1561

3122

4683

6244

7805

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

458

916

1374

1832

2290

<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:

0.256

Hom.:

17332

Bravo

AF:

0.339

TwinsUK

AF:

0.221

AC:

819

ALSPAC

AF:

0.231

AC:

892

ESP6500AA

AF:

0.599

AC:

2639

ESP6500EA

AF:

0.223

AC:

1919

ExAC

AF:

0.249

AC:

30260

Asia WGS

AF:

0.249

AC:

864

AN:

3478

EpiCase

AF:

0.229

EpiControl

AF:

0.226

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.012

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.30

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.24

MetaRNN

Benign

0.000031

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.2

PhyloP100

0.76

PrimateAI

Benign

0.35

PROVEAN

Uncertain

-3.0

Sift

Uncertain

0.0080

Sift4G

Pathogenic

0.0

Polyphen

0.98

Vest4

0.11

ClinPred

0.032

GERP RS

2.5

PromoterAI

0.042

Neutral

(source)

Varity_R

0.31

gMVP

0.71

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

Computational scores

Splicing

Publications

Other links and lift over