rs189395138

Variant names:

• chr2-197488500-G-A
• rs189395138
• NM_002156.5:c.1216-9C>T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_002156.5(HSPD1):​c.1216-9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00263 in 1,611,940 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0026 (13 hom.)
• Consequence: HSPD1 NM_002156.5 intron
• Scores: Splicing: ADA: 0.000009175
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.965

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 2-197488500-G-A is Benign according to our data. Variant chr2-197488500-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 137562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPD1	NM_002156.5	c.1216-9C>T		intron_variant	Intron 9 of 11	ENST00000388968.8	NP_002147.2
HSPD1	NM_199440.2	c.1216-9C>T		intron_variant	Intron 9 of 11		NP_955472.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSPD1	ENST00000388968.8	c.1216-9C>T		intron_variant	Intron 9 of 11	1	NM_002156.5	ENSP00000373620.3

Frequencies

GnomAD3 genomes AF: 0.00339 AC: 516 AN: 152116 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0163

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00471

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00323 AC: 811 AN: 250704 Hom.: 3 AF XY: 0.00313 AC XY: 424 AN XY: 135494

Gnomad AFR exome AF: 0.000310

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00477

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0149

Gnomad NFE exome AF: 0.00357

Gnomad OTH exome AF: 0.00441

GnomAD4 exome AF: 0.00255 AC: 3729 AN: 1459706 Hom.: 13 Cov.: 30 AF XY: 0.00255 AC XY: 1854 AN XY: 726382

Gnomad4 AFR exome AF: 0.000150

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00486

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0145

Gnomad4 NFE exome AF: 0.00242

Gnomad4 OTH exome AF: 0.00222

GnomAD4 genome AF: 0.00339 AC: 516 AN: 152234 Hom.: 5 Cov.: 33 AF XY: 0.00398 AC XY: 296 AN XY: 74438

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.0163

Gnomad4 NFE AF: 0.00471

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00497 Hom.: 3

Bravo AF: 0.00133

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Aug 26, 2024

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 30, 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. -

Spastic paraplegia Benign:1

Jan 26, 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 13, 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: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Aug 24, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.5
DANN	Benign	0.38

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000092
dbscSNV1_RF	Benign	0.018
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: rs189395138; hg19: chr2-198353224;