chr2-197498822-G-C

Variant names:

• chr2-197498822-G-C
• rs11551349
• NM_002156.5:c.27C>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_002156.5(HSPD1):​c.27C>G​(p.Arg9Arg) 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 NM_002156.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: -0.232
• Publications: 3 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 -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 VariationId is 129242.
• BP7: Synonymous conserved (PhyloP=-0.232 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 51 AR,AD gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPD1	NM_002156.5	MANE Select	c.27C>G	p.Arg9Arg	synonymous	Exon 2 of 12	NP_002147.2
	HSPD1	NM_199440.2		c.27C>G	p.Arg9Arg	synonymous	Exon 2 of 12	NP_955472.1	A0A024R3X4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPD1	ENST00000388968.8	TSL:1 MANE Select	c.27C>G	p.Arg9Arg	synonymous	Exon 2 of 12	ENSP00000373620.3	P10809-1
	HSPD1	ENST00000954440.1		c.27C>G	p.Arg9Arg	synonymous	Exon 2 of 12	ENSP00000624499.1
	HSPD1	ENST00000345042.6	TSL:5	c.27C>G	p.Arg9Arg	synonymous	Exon 2 of 12	ENSP00000340019.2	P10809-1

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

GnomAD2 exomes AF: 0.00488 AC: 1227 AN: 251374 AF XY: 0.00523

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 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

African (AFR) AF: 0.000986 AC: 33 AN: 33480

American (AMR) AF: 0.00300 AC: 134 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000344 AC: 9 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00820 AC: 707 AN: 86258

European-Finnish (FIN) AF: 0.00506 AC: 270 AN: 53402

Middle Eastern (MID) AF: 0.00537 AC: 31 AN: 5768

European-Non Finnish (NFE) AF: 0.00734 AC: 8167 AN: 1111972

Other (OTH) AF: 0.00634 AC: 383 AN: 60392

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

African (AFR) AF: 0.00128 AC: 53 AN: 41560

American (AMR) AF: 0.00235 AC: 36 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00642 AC: 31 AN: 4832

European-Finnish (FIN) AF: 0.00509 AC: 54 AN: 10610

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00792 AC: 539 AN: 68032

Other (OTH) AF: 0.00851 AC: 18 AN: 2116

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

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	1	2	not provided (3)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	Hereditary spastic paraplegia 13 (1)
-	-	1	HSPD1-related disorder (1)
-	-	1	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	9.7
DANN	Benign	0.79
PhyloP100		-0.23
Mutation Taster		=99/1	polymorphism

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: rs11551349; hg19: chr2-198363546;