chr12-119179428-C-G

Variant names:

• chr12-119179428-C-G
• NM_014365.3:c.116C>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_014365.3(HSPB8):​c.116C>G​(p.Pro39Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,860 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HSPB8 NM_014365.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.43

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a chain Heat shock protein beta-8 (size 195) in uniprot entity HSPB8_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_014365.3
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPB8	NM_014365.3	c.116C>G	p.Pro39Arg	missense_variant	Exon 1 of 3	ENST00000281938.7	NP_055180.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSPB8	ENST00000281938.7	c.116C>G	p.Pro39Arg	missense_variant	Exon 1 of 3	1	NM_014365.3	ENSP00000281938.3
HSPB8	ENST00000674542.1	c.116C>G	p.Pro39Arg	missense_variant	Exon 1 of 2			ENSP00000502352.1
HSPB8	ENST00000676244.1	n.73+5430C>G		intron_variant	Intron 1 of 2
HSPB8	ENST00000541798.1	c.-164C>G		upstream_gene_variant		3		ENSP00000441541.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461860 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727236

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Benign	1.0	L
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.58
Sift	Benign	0.56	T
Sift4G	Benign	0.66	T
Polyphen		0.95	P
Vest4		0.49
MutPred		0.37		Gain of catalytic residue at M37 (P = 0);
MVP		0.99
MPC		0.83
ClinPred		0.92	D
GERP RS		4.4
Varity_R		0.35
gMVP		0.84

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-119617233;