2-197496162-A-G

Variant names:

• chr2-197496162-A-G
• rs2340690
• NM_002156.5:c.428-786T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002156.5(HSPD1):​c.428-786T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 152,202 control chromosomes in the GnomAD database, including 2,155 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.16 (2155 hom., cov: 32)
• Consequence: HSPD1 NM_002156.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.959
• Publications: 11 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.229 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPD1	NM_002156.5	c.428-786T>C		intron_variant	Intron 3 of 11	ENST00000388968.8	NP_002147.2
HSPD1	NM_199440.2	c.428-786T>C		intron_variant	Intron 3 of 11		NP_955472.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSPD1	ENST00000388968.8	c.428-786T>C		intron_variant	Intron 3 of 11	1	NM_002156.5	ENSP00000373620.3

Frequencies

GnomAD3 genomes AF: 0.158 AC: 24027 AN: 152084 Hom.: 2151 Cov.: 32

Gnomad AFR AF: 0.0756

Gnomad AMI AF: 0.196

Gnomad AMR AF: 0.192

Gnomad ASJ AF: 0.235

Gnomad EAS AF: 0.239

Gnomad SAS AF: 0.117

Gnomad FIN AF: 0.185

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.187

Gnomad OTH AF: 0.183

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.158 AC: 24045 AN: 152202 Hom.: 2155 Cov.: 32 AF XY: 0.159 AC XY: 11854 AN XY: 74412

African (AFR) AF: 0.0755 AC: 3137 AN: 41540

American (AMR) AF: 0.192 AC: 2933 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.235 AC: 815 AN: 3470

East Asian (EAS) AF: 0.240 AC: 1245 AN: 5186

South Asian (SAS) AF: 0.119 AC: 573 AN: 4826

European-Finnish (FIN) AF: 0.185 AC: 1953 AN: 10578

Middle Eastern (MID) AF: 0.279 AC: 82 AN: 294

European-Non Finnish (NFE) AF: 0.187 AC: 12738 AN: 68002

Other (OTH) AF: 0.185 AC: 390 AN: 2108

Alfa AF: 0.185 Hom.: 3195

Bravo AF: 0.159

Asia WGS AF: 0.171 AC: 596 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	11
DANN	Benign	0.85
PhyloP100		0.96
Mutation Taster		=100/0	polymorphism (auto)

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: rs2340690; hg19: chr2-198360886;