Genetic Variant HSPB6:p.Glu104Lys (chr19-35755783-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_144617.3(HSPB6):c.310G>A(p.Glu104Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000156 in 1,586,956 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

HSPB6
NM_144617.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.86

Variant links:

Genes affected

HSPB6 (HGNC:26511): (heat shock protein family B (small) member 6) This locus encodes a heat shock protein. The encoded protein likely plays a role in smooth muscle relaxation. [provided by RefSeq, Jan 2012]

HSPB6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPB6	NM_144617.3 link	c.310G>A	p.Glu104Lys	missense_variant	Exon 2 of 3	ENST00000004982.6	NP_653218.1	O14558V9HWB6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HSPB6	ENST00000004982.6 link	c.310G>A	p.Glu104Lys	missense_variant	Exon 2 of 3	1	NM_144617.3	ENSP00000004982.3	O14558
HSPB6	ENST00000587965.1 link	c.310G>A	p.Glu104Lys	missense_variant	Exon 2 of 2	2		ENSP00000467169.1	K7EP04
HSPB6	ENST00000592984.6 link	c.310G>A	p.Glu104Lys	missense_variant	Exon 3 of 4	4		ENSP00000468057.2	A0A1X7SC65

Frequencies

GnomAD3 genomes

AF:

0.000191

AC:

AN:

151970

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:

0.000412

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000121

AC:

AN:

198804

Hom.:

AF XY:

0.000120

AC XY:

AN XY:

108676

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:

0.0000382

Gnomad FIN exome

AF:

0.000112

Gnomad NFE exome

AF:

0.000226

Gnomad OTH exome

AF:

0.000405

GnomAD4 exome

AF:

0.000152

AC:

218

AN:

1434986

Hom.:

Cov.:

AF XY:

0.000163

AC XY:

116

AN XY:

711730

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000243

Gnomad4 FIN exome

AF:

0.000178

Gnomad4 NFE exome

AF:

0.000175

Gnomad4 OTH exome

AF:

0.000220

GnomAD4 genome

AF:

0.000191

AC:

AN:

151970

Hom.:

Cov.:

AF XY:

0.000189

AC XY:

AN XY:

74216

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000412

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000348

Hom.:

Bravo

AF:

0.000110

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000235

AC:

ExAC

AF:

0.000143

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 04, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.310G>A (p.E104K) alteration is located in exon 2 (coding exon 2) of the HSPB6 gene. This alteration results from a G to A substitution at nucleotide position 310, causing the glutamic acid (E) at amino acid position 104 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

-0.050

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.77

D;D;.

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.77

LIST_S2

Uncertain

0.91

D;T;D

M_CAP

Uncertain

0.21

MetaRNN

Uncertain

0.46

T;T;T

MetaSVM

Uncertain

0.50

MutationAssessor

Benign

1.9

L;.;.

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-2.9

D;.;.

REVEL

Pathogenic

0.74

Sift

Uncertain

0.020

D;.;.

Sift4G

Uncertain

0.025

D;D;D

Polyphen

0.88

P;.;.

Vest4

0.52

MVP

0.97

MPC

0.99

ClinPred

0.27

GERP RS

4.4

Varity_R

0.62

gMVP

0.76

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