12-119179337-T-C

Variant names:

• chr12-119179337-T-C
• rs774233360
• NM_014365.3:c.25T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014365.3(HSPB8):​c.25T>C​(p.Ser9Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S9F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HSPB8 NM_014365.3 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: -0.395
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• neuronopathy, distal hereditary motor, autosomal dominant

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Charcot-Marie-Tooth disease axonal type 2L

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• neuronopathy, distal hereditary motor, type 2A

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• autosomal dominant distal axonal motor neuropathy-myofibrillar myopathy syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• distal hereditary motor neuropathy type 2

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.064599216).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014365.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPB8	NM_014365.3	MANE Select	c.25T>C	p.Ser9Pro	missense	Exon 1 of 3	NP_055180.1	Q9UJY1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPB8	ENST00000281938.7	TSL:1 MANE Select	c.25T>C	p.Ser9Pro	missense	Exon 1 of 3	ENSP00000281938.3	Q9UJY1
	HSPB8	ENST00000674542.1		c.25T>C	p.Ser9Pro	missense	Exon 1 of 2	ENSP00000502352.1	A0A6Q8PGM6
	HSPB8	ENST00000676244.1		n.73+5339T>C		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000763 AC: 19 AN: 249094 AF XY: 0.0000148

Gnomad AFR exome AF: 0.000320

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: 0.000124

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000130 AC: 19 AN: 1460834 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 726772

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.000362 AC: 19 AN: 52434

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111976

Other (OTH) AF: 0.00 AC: 0 AN: 60362

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000824 AC: 10

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	Charcot-Marie-Tooth disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	15
DANN	Uncertain	0.97
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.49	T
M_CAP	Uncertain	0.092	D
MetaRNN	Benign	0.065	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	0.83	L
PhyloP100		-0.40
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.28
Sift	Benign	0.13	T
Sift4G	Benign	0.14	T
Polyphen		0.0	B
Vest4		0.12
MVP		0.90
MPC		0.29
ClinPred		0.035	T
GERP RS		-2.4
PromoterAI		-0.048	Neutral
Varity_R		0.15
gMVP		0.67
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs774233360; hg19: chr12-119617142;