rs104894351

Variant names:

• chr12-119187078-A-C
• rs104894351
• NM_014365.3:c.421A>C

Your query was ambiguous. Multiple possible variants found:

• chr12-119187078-A-C
• chr12-119187078-A-G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_014365.3(HSPB8):​c.421A>C​(p.Lys141Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K141T) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HSPB8 NM_014365.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.36
• Publications: 49 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_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_014365.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-119187079-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 637689.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.932

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.421A>C	p.Lys141Gln	missense	Exon 2 of 3	NP_055180.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPB8	ENST00000281938.7	TSL:1 MANE Select	c.421A>C	p.Lys141Gln	missense	Exon 2 of 3	ENSP00000281938.3
	HSPB8	ENST00000541798.1	TSL:3	c.142A>C	p.Lys48Gln	missense	Exon 2 of 4	ENSP00000441541.1
	HSPB8	ENST00000674763.1		c.52A>C	p.Lys18Gln	missense	Exon 1 of 3	ENSP00000502573.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Charcot-Marie-Tooth disease axonal type 2L (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.1	L
PhyloP100		8.4
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.6	N
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.010	D
Polyphen		0.99	D
Vest4		0.90
MutPred		0.81		Loss of methylation at K141 (P = 0.0146)
MVP		0.99
MPC		0.89
ClinPred		0.92	D
GERP RS		5.7
PromoterAI		0.013	Neutral
Varity_R		0.63
gMVP		0.74
Mutation Taster		=54/46	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: rs104894351; hg19: chr12-119624883;