chr2-197498780-A-G

Variant names:

• chr2-197498780-A-G
• rs1050347
• NM_002156.5:c.69T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002156.5(HSPD1):​c.69T>C​(p.Thr23Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.181 in 1,609,464 control chromosomes in the GnomAD database, including 24,827 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2307 hom., cov: 33)
  • Exomes 𝑓: 0.18 (22520 hom.)
• Consequence: HSPD1 NM_002156.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.182
• Publications: 23 publications found

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 Gene-Disease associations (from GenCC):

• hereditary spastic paraplegia 13

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hypomyelinating leukodystrophy 4

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 2-197498780-A-G is Benign according to our data. Variant chr2-197498780-A-G is described in ClinVar as Benign. ClinVar VariationId is 129243.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.182 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.229 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002156.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPD1	NM_002156.5	MANE Select	c.69T>C	p.Thr23Thr	synonymous	Exon 2 of 12	NP_002147.2
	HSPD1	NM_199440.2		c.69T>C	p.Thr23Thr	synonymous	Exon 2 of 12	NP_955472.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPD1	ENST00000388968.8	TSL:1 MANE Select	c.69T>C	p.Thr23Thr	synonymous	Exon 2 of 12	ENSP00000373620.3
	HSPD1	ENST00000345042.6	TSL:5	c.69T>C	p.Thr23Thr	synonymous	Exon 2 of 12	ENSP00000340019.2
	HSPD1	ENST00000418022.2	TSL:4	c.69T>C	p.Thr23Thr	synonymous	Exon 3 of 13	ENSP00000412227.2

Frequencies

GnomAD3 genomes AF: 0.168 AC: 25580 AN: 152092 Hom.: 2304 Cov.: 33

Gnomad AFR AF: 0.110

Gnomad AMI AF: 0.196

Gnomad AMR AF: 0.197

Gnomad ASJ AF: 0.235

Gnomad EAS AF: 0.239

Gnomad SAS AF: 0.117

Gnomad FIN AF: 0.184

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.188

Gnomad OTH AF: 0.195

GnomAD2 exomes AF: 0.173 AC: 43350 AN: 250876 AF XY: 0.172

Gnomad AFR exome AF: 0.105

Gnomad AMR exome AF: 0.185

Gnomad ASJ exome AF: 0.219

Gnomad EAS exome AF: 0.230

Gnomad FIN exome AF: 0.178

Gnomad NFE exome AF: 0.179

Gnomad OTH exome AF: 0.202

GnomAD4 exome AF: 0.182 AC: 265548 AN: 1457254 Hom.: 22520 Cov.: 34 AF XY: 0.181 AC XY: 131249 AN XY: 725130

African (AFR) AF: 0.106 AC: 3549 AN: 33438

American (AMR) AF: 0.191 AC: 8519 AN: 44626

Ashkenazi Jewish (ASJ) AF: 0.232 AC: 6058 AN: 26088

East Asian (EAS) AF: 0.233 AC: 9232 AN: 39636

South Asian (SAS) AF: 0.117 AC: 10059 AN: 86204

European-Finnish (FIN) AF: 0.184 AC: 9839 AN: 53392

Middle Eastern (MID) AF: 0.228 AC: 1314 AN: 5754

European-Non Finnish (NFE) AF: 0.186 AC: 205909 AN: 1107874

Other (OTH) AF: 0.184 AC: 11069 AN: 60242

GnomAD4 genome AF: 0.168 AC: 25611 AN: 152210 Hom.: 2307 Cov.: 33 AF XY: 0.169 AC XY: 12581 AN XY: 74414

African (AFR) AF: 0.110 AC: 4581 AN: 41544

American (AMR) AF: 0.197 AC: 3006 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.235 AC: 814 AN: 3470

East Asian (EAS) AF: 0.240 AC: 1240 AN: 5172

South Asian (SAS) AF: 0.118 AC: 571 AN: 4826

European-Finnish (FIN) AF: 0.184 AC: 1952 AN: 10590

Middle Eastern (MID) AF: 0.282 AC: 83 AN: 294

European-Non Finnish (NFE) AF: 0.188 AC: 12770 AN: 68002

Other (OTH) AF: 0.197 AC: 415 AN: 2110

Alfa AF: 0.175 Hom.: 916

Bravo AF: 0.170

Asia WGS AF: 0.176 AC: 611 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Oct 25, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed.

Spastic paraplegia Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary spastic paraplegia 13 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Hereditary spastic paraplegia Benign:1

Dec 12, 2016

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	13
DANN	Benign	0.81
PhyloP100		0.18
Mutation Taster		=100/0	polymorphism (auto)

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: rs1050347; hg19: chr2-198363504; COSMIC: COSV52098088; COSMIC: COSV52098088;