12-119179545-G-T

Position:

chr12-119179545-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 2P and 14B. PM1BP4_ModerateBP6_Very_StrongBS2

The NM_014365.3(HSPB8):c.233G>T(p.Arg78Met) variant causes a missense change. The variant allele was found at a frequency of 0.000816 in 1,613,678 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00054 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00084 ( 1 hom. )

Consequence

HSPB8
NM_014365.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 5.63

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:

HSPB8 (HGNC:):

HSPB8 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

PM1

In a modified_residue Asymmetric dimethylarginine (size 0) in uniprot entity HSPB8_HUMAN

BP4

Computational evidence support a benign effect (MetaRNN=0.113461316).

BP6

Variant 12-119179545-G-T is Benign according to our data. Variant chr12-119179545-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 380971.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 83 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSPB8	NM_014365.3 linkuse as main transcript	c.233G>T	p.Arg78Met	missense_variant	1/3	ENST00000281938.7	NP_055180.1	Q9UJY1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
HSPB8	ENST00000281938.7 linkuse as main transcript	c.233G>T	p.Arg78Met	missense_variant	1/3	1	NM_014365.3	ENSP00000281938.3	Q9UJY1
HSPB8	ENST00000674542.1 linkuse as main transcript	c.233G>T	p.Arg78Met	missense_variant	1/2			ENSP00000502352.1	A0A6Q8PGM6
HSPB8	ENST00000676244.1 linkuse as main transcript	n.73+5547G>T		intron_variant
HSPB8	ENST00000541798.1 linkuse as main transcript	c.-47G>T		upstream_gene_variant		3		ENSP00000441541.1	H0YG30

Frequencies

GnomAD3 genomes

AF:

0.000545

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000916

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000853

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000638

AC:

159

AN:

249156

Hom.:

AF XY:

0.000645

AC XY:

AN XY:

134986

show subpopulations

Gnomad AFR exome

AF:

0.000127

Gnomad AMR exome

AF:

0.000464

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.000325

Gnomad NFE exome

AF:

0.00115

Gnomad OTH exome

AF:

0.000493

GnomAD4 exome

AF:

0.000844

AC:

1234

AN:

1461358

Hom.:

Cov.:

AF XY:

0.000813

AC XY:

591

AN XY:

726966

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.000358

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.000507

Gnomad4 NFE exome

AF:

0.00102

Gnomad4 OTH exome

AF:

0.000762

GnomAD4 genome

AF:

0.000545

AC:

AN:

152320

Hom.:

Cov.:

AF XY:

0.000604

AC XY:

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.000192

Gnomad4 AMR

AF:

0.000915

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.000853

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000812

Hom.:

Bravo

AF:

0.000487

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000684

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	HSPB8: BS1 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 09, 2019	This variant is associated with the following publications: (PMID: 24717127) -

Charcot-Marie-Tooth disease axonal type 2L

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 19, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Aug 06, 2024

- -

Neuronopathy, distal hereditary motor, type 2A

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Sep 19, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 20, 2019

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

Uncertain

0.37

BayesDel_addAF

Benign

-0.070

BayesDel_noAF

Uncertain

0.080

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.094

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.58

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.11

MetaSVM

Uncertain

0.0098

MutationAssessor

Benign

1.9

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-0.19

REVEL

Uncertain

0.48

Sift

Benign

0.17

Sift4G

Benign

0.23

Polyphen

0.84

Vest4

0.47

MVP

1.0

MPC

0.68

ClinPred

0.032

GERP RS

4.4

Varity_R

0.18

gMVP

0.75

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