2-197487080-C-G

Position:

chr2-197487080-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 6.98

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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/exons	MANE	UniProt
HSPD1	NM_002156.5 linkuse as main transcript	c.1688G>C	p.Gly563Ala	missense_variant	12/12	ENST00000388968.8
HSPD1	NM_199440.2 linkuse as main transcript	c.1688G>C	p.Gly563Ala	missense_variant	12/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSPD1	ENST00000388968.8 linkuse as main transcript	c.1688G>C	p.Gly563Ala	missense_variant	12/12	1	NM_002156.5	P1	P10809-1

Frequencies

GnomAD3 genomes

AF:

0.0158

AC:

2396

AN:

152086

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.0175

AC XY:

2360

AN XY:

134530

show subpopulations

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.:

AF XY:

0.0196

AC XY:

13521

AN XY:

688938

show subpopulations

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.:

Cov.:

AF XY:

0.0167

AC XY:

1242

AN XY:

74422

show subpopulations

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.:

Bravo

AF:

0.0129

ESP6500AA

AF:

0.00305

AC:

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

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 15, 2019	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 12, 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 12, 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

Jan 14, 2022

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.83

D;D

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.92

.;D

MetaRNN

Benign

0.0087

T;T

MetaSVM

Uncertain

-0.17

MutationAssessor

Uncertain

2.9

M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.71

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over