rs4628742

chr12-119193849-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_014365.3(HSPB8):c.582C>T(p.Thr194=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0139 in 1,614,058 control chromosomes in the GnomAD database, including 2,348 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.069 (1239 hom., cov: 32)
  • Exomes 𝑓: 0.0081 (1109 hom.)
• Consequence: HSPB8 NM_014365.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.280

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 12-119193849-C-T is Benign according to our data. Variant chr12-119193849-C-T is described in ClinVar as [Benign]. Clinvar id is 260403.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-119193849-C-T is described in Lovd as [Benign]. Variant chr12-119193849-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.28 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.235 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSPB8	NM_014365.3	c.582C>T	p.Thr194=	synonymous_variant	3/3	ENST00000281938.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSPB8	ENST00000281938.7	c.582C>T	p.Thr194=	synonymous_variant	3/3	1	NM_014365.3	P1

Frequencies

GnomAD3 genomes AF: 0.0691 AC: 10515 AN: 152102 Hom.: 1230 Cov.: 32

Gnomad AFR AF: 0.239

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0225

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0183

Gnomad SAS AF: 0.0108

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000706

Gnomad OTH AF: 0.0435

GnomAD3 exomes AF: 0.0206 AC: 5171 AN: 251490 Hom.: 534 AF XY: 0.0163 AC XY: 2211 AN XY: 135920

Gnomad AFR exome AF: 0.248

Gnomad AMR exome AF: 0.0106

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.0191

Gnomad SAS exome AF: 0.00944

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000659

Gnomad OTH exome AF: 0.0101

GnomAD4 exome AF: 0.00813 AC: 11884 AN: 1461838 Hom.: 1109 Cov.: 31 AF XY: 0.00732 AC XY: 5325 AN XY: 727230

Gnomad4 AFR exome AF: 0.246

Gnomad4 AMR exome AF: 0.0121

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0198

Gnomad4 SAS exome AF: 0.00925

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000325

Gnomad4 OTH exome AF: 0.0180

GnomAD4 genome AF: 0.0693 AC: 10550 AN: 152220 Hom.: 1239 Cov.: 32 AF XY: 0.0674 AC XY: 5020 AN XY: 74434

Gnomad4 AFR AF: 0.239

Gnomad4 AMR AF: 0.0225

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0184

Gnomad4 SAS AF: 0.0106

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000706

Gnomad4 OTH AF: 0.0430

Alfa AF: 0.0195 Hom.: 432

Bravo AF: 0.0783

Asia WGS AF: 0.0360 AC: 124 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000830

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 27, 2017	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 13, 2016	- -

Charcot-Marie-Tooth disease axonal type 2L Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Neuronopathy, distal hereditary motor, type 2A Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

This variant is associated with the following publications: (PMID: 16155736, 27884173, 16086267, 20981092) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
Cadd	Benign	7.6
Dann	Benign	0.73

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

Other links and lift over

dbSNP: rs4628742; hg19: chr12-119631654;