rs864622156

Positions:

• chr2-197494160-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002156.5(HSPD1):​c.697A>C​(p.Lys233Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HSPD1 NM_002156.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.86

Genes affected

HSPD1 (HGNC:5261): (heat shock protein family D (Hsp60) member 1) This gene encodes a member of the chaperonin family. The encoded mitochondrial protein may function as a signaling molecule in the innate immune system. This protein is essential for the folding and assembly of newly imported proteins in the mitochondria. This gene is adjacent to a related family member and the region between the 2 genes functions as a bidirectional promoter. Several pseudogenes have been associated with this gene. Two transcript variants encoding the same protein have been identified for this gene. Mutations associated with this gene cause autosomal recessive spastic paraplegia 13. [provided by RefSeq, Jun 2010]

HSPD1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSPD1	NM_002156.5	c.697A>C	p.Lys233Gln	missense_variant	6/12	ENST00000388968.8	NP_002147.2
HSPD1	NM_199440.2	c.697A>C	p.Lys233Gln	missense_variant	6/12		NP_955472.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSPD1	ENST00000388968.8	c.697A>C	p.Lys233Gln	missense_variant	6/12	1	NM_002156.5	ENSP00000373620.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 16

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Spastic paraplegia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 18, 2015

This variant has not been published in the literature and is not present in population databases. This sequence change replaces lysine with glutamine at codon 233 of the HSPD1 protein (p.Lys233Gln). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and glutamine. In summary, this is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;D;T
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	.;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.62	D;D;D
MetaSVM	Uncertain	0.37	D
MutationAssessor	Uncertain	2.4	M;M;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.7	D;D;D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0010	D;D;D
Sift4G	Benign	0.061	T;T;.
Polyphen		0.99	D;D;.
Vest4		0.46
MutPred		0.43		Loss of methylation at K233 (P = 0.007);Loss of methylation at K233 (P = 0.007);.;
MVP		0.72
MPC		1.7
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.98
gMVP		0.68

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: rs864622156; hg19: chr2-198358884;