NM_002156.5:c.1688G>C

Variant names:

• chr2-197487080-C-G
• rs41265953
• NM_002156.5:c.1688G>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002156.5(HSPD1):​c.1688G>C​(p.Gly563Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0195 in 1,526,954 control chromosomes in the GnomAD database, including 399 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (26 hom., cov: 32)
  • Exomes 𝑓: 0.020 (373 hom.)
• Consequence: HSPD1 NM_002156.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 6.98

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008711159).
• BP6: Variant 2-197487080-C-G is Benign according to our data. Variant chr2-197487080-C-G is described in ClinVar as [Benign]. Clinvar id is 137563.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-197487080-C-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0157 (2397/152204) while in subpopulation NFE AF= 0.021 (1429/67990). AF 95% confidence interval is 0.0201. There are 26 homozygotes in gnomad4. There are 1242 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 26 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPD1	NM_002156.5	c.1688G>C	p.Gly563Ala	missense_variant	Exon 12 of 12	ENST00000388968.8	NP_002147.2
HSPD1	NM_199440.2	c.1688G>C	p.Gly563Ala	missense_variant	Exon 12 of 12		NP_955472.1
SNORA105B	NR_132788.1	n.-177G>C		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSPD1	ENST00000388968.8	c.1688G>C	p.Gly563Ala	missense_variant	Exon 12 of 12	1	NM_002156.5	ENSP00000373620.3

Frequencies

GnomAD3 genomes AF: 0.0158 AC: 2396 AN: 152086 Hom.: 26 Cov.: 32

Gnomad AFR AF: 0.00290

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0119

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00869

Gnomad FIN AF: 0.0499

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0210

Gnomad OTH AF: 0.0167

GnomAD3 exomes AF: 0.0167 AC: 4126 AN: 246966 Hom.: 52 AF XY: 0.0175 AC XY: 2360 AN XY: 134530

Gnomad AFR exome AF: 0.00238

Gnomad AMR exome AF: 0.00681

Gnomad ASJ exome AF: 0.0140

Gnomad EAS exome AF: 0.000164

Gnomad SAS exome AF: 0.0107

Gnomad FIN exome AF: 0.0497

Gnomad NFE exome AF: 0.0199

Gnomad OTH exome AF: 0.0160

GnomAD4 exome AF: 0.0200 AC: 27431 AN: 1374750 Hom.: 373 Cov.: 22 AF XY: 0.0196 AC XY: 13521 AN XY: 688938

Gnomad4 AFR exome AF: 0.00275

Gnomad4 AMR exome AF: 0.00734

Gnomad4 ASJ exome AF: 0.0160

Gnomad4 EAS exome AF: 0.000102

Gnomad4 SAS exome AF: 0.0114

Gnomad4 FIN exome AF: 0.0476

Gnomad4 NFE exome AF: 0.0213

Gnomad4 OTH exome AF: 0.0191

GnomAD4 genome AF: 0.0157 AC: 2397 AN: 152204 Hom.: 26 Cov.: 32 AF XY: 0.0167 AC XY: 1242 AN XY: 74422

Gnomad4 AFR AF: 0.00289

Gnomad4 AMR AF: 0.0119

Gnomad4 ASJ AF: 0.0156

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00870

Gnomad4 FIN AF: 0.0499

Gnomad4 NFE AF: 0.0210

Gnomad4 OTH AF: 0.0166

Alfa AF: 0.0174 Hom.: 6

Bravo AF: 0.0129

ESP6500AA AF: 0.00305 AC: 13

ESP6500EA AF: 0.0169 AC: 142

ExAC AF: 0.0161 AC: 1943

EpiCase AF: 0.0190

EpiControl AF: 0.0175

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Nov 13, 2023

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 12, 2014

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 28, 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

Jan 14, 2022

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 v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.83	D;D
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	.;D
MetaRNN	Benign	0.0087	T;T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Uncertain	2.9	M;M
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-4.1	D;D
REVEL	Uncertain	0.55
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.015	D;D
Polyphen		1.0	D;D
Vest4		0.20
MPC		2.0
ClinPred		0.030	T
GERP RS		5.2
Varity_R		0.73
gMVP		0.76

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: rs41265953; hg19: chr2-198351804; COSMIC: COSV61445925; COSMIC: COSV61445925;