2-197498822-G-C

Position:

• chr2-197498822-G-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The ENST00000388968.8(HSPD1):​c.27C>G​(p.Arg9=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0065 in 1,614,142 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R9R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0049 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0067 (51 hom.)
• Consequence: HSPD1 ENST00000388968.8 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: -0.232

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 2-197498822-G-C is Benign according to our data. Variant chr2-197498822-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 129242.We mark this variant Likely_benign, oryginal submissions are: {Benign=5, Uncertain_significance=1, Likely_benign=1}. Variant chr2-197498822-G-C is described in Lovd as [Likely_benign]. Variant chr2-197498822-G-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.232 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 51 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSPD1	NM_002156.5	c.27C>G	p.Arg9=	synonymous_variant	2/12	ENST00000388968.8	NP_002147.2
HSPD1	NM_199440.2	c.27C>G	p.Arg9=	synonymous_variant	2/12		NP_955472.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSPD1	ENST00000388968.8	c.27C>G	p.Arg9=	synonymous_variant	2/12	1	NM_002156.5	ENSP00000373620	P1

Frequencies

GnomAD3 genomes AF: 0.00490 AC: 746 AN: 152192 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00600

Gnomad FIN AF: 0.00509

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00792

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.00488 AC: 1227 AN: 251374 Hom.: 8 AF XY: 0.00523 AC XY: 711 AN XY: 135888

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.00266

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00784

Gnomad FIN exome AF: 0.00430

Gnomad NFE exome AF: 0.00654

Gnomad OTH exome AF: 0.00554

GnomAD4 exome AF: 0.00666 AC: 9736 AN: 1461832 Hom.: 51 Cov.: 33 AF XY: 0.00679 AC XY: 4936 AN XY: 727224

Gnomad4 AFR exome AF: 0.000986

Gnomad4 AMR exome AF: 0.00300

Gnomad4 ASJ exome AF: 0.000344

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00820

Gnomad4 FIN exome AF: 0.00506

Gnomad4 NFE exome AF: 0.00734

Gnomad4 OTH exome AF: 0.00634

GnomAD4 genome AF: 0.00491 AC: 748 AN: 152310 Hom.: 1 Cov.: 33 AF XY: 0.00477 AC XY: 355 AN XY: 74478

Gnomad4 AFR AF: 0.00128

Gnomad4 AMR AF: 0.00235

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00642

Gnomad4 FIN AF: 0.00509

Gnomad4 NFE AF: 0.00792

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.00525 Hom.: 1

Bravo AF: 0.00429

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00654

EpiControl AF: 0.00658

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 06, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	HSPD1: BP4, BP7, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 04, 2020	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 28, 2014	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. -

Spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Hereditary spastic paraplegia 13 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 09, 2021

- -

HSPD1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 03, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	9.7
DANN	Benign	0.79

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: rs11551349; hg19: chr2-198363546;