2-197487066-T-C

Variant names:

• chr2-197487066-T-C
• rs757331948
• NM_002156.5:c.1702A>G

Variant summary

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

The NM_002156.5(HSPD1):​c.1702A>G​(p.Met568Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000464 in 1,508,944 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000037 (0 hom.)
• Consequence: HSPD1 NM_002156.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.45

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]

SNORA105B (HGNC:51398): (small nucleolar RNA, H/ACA box 105B)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPD1	NM_002156.5	c.1702A>G	p.Met568Val	missense_variant	Exon 12 of 12	ENST00000388968.8	NP_002147.2
HSPD1	NM_199440.2	c.1702A>G	p.Met568Val	missense_variant	Exon 12 of 12		NP_955472.1
SNORA105B	NR_132788.1	n.-163A>G		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSPD1	ENST00000388968.8	c.1702A>G	p.Met568Val	missense_variant	Exon 12 of 12	1	NM_002156.5	ENSP00000373620.3

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152070 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000122 AC: 3 AN: 246882 Hom.: 0 AF XY: 0.0000149 AC XY: 2 AN XY: 134460

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000180

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000368 AC: 5 AN: 1356874 Hom.: 0 Cov.: 21 AF XY: 0.00000587 AC XY: 4 AN XY: 680940

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000225

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: 0.00000394

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152070 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74286

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Spastic paraplegia Uncertain:1

Oct 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 568 of the HSPD1 protein (p.Met568Val). This variant is present in population databases (rs757331948, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with HSPD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1415601). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	23
DANN	Benign	0.95
DEOGEN2	Pathogenic	0.84	D;D
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.69	.;T
M_CAP	Benign	0.053	D
MetaRNN	Uncertain	0.58	D;D
MetaSVM	Benign	-0.45	T
MutationAssessor	Pathogenic	3.6	H;H
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.6	D;D
REVEL	Uncertain	0.59
Sift	Benign	0.30	T;T
Sift4G	Uncertain	0.019	D;D
Polyphen		0.32	B;B
Vest4		0.65
MutPred		0.45		Gain of catalytic residue at M568 (P = 0.0721);Gain of catalytic residue at M568 (P = 0.0721);
MVP		0.72
MPC		1.9
ClinPred		0.38	T
GERP RS		5.2
Varity_R		0.33
gMVP		0.80

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: rs757331948; hg19: chr2-198351790;