NM_002156.5:c.607-53C>G

Variant names:

• chr2-197494303-G-C
• rs7585486
• NM_002156.5:c.607-53C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002156.5(HSPD1):​c.607-53C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.163 in 899,428 control chromosomes in the GnomAD database, including 13,129 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1841 hom., cov: 32)
  • Exomes 𝑓: 0.17 (11288 hom.)
• Consequence: HSPD1 NM_002156.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.87
• Publications: 7 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 2-197494303-G-C is Benign according to our data. Variant chr2-197494303-G-C is described in ClinVar as Benign. ClinVar VariationId is 671556.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.221 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPD1	NM_002156.5	c.607-53C>G		intron_variant	Intron 5 of 11	ENST00000388968.8	NP_002147.2
HSPD1	NM_199440.2	c.607-53C>G		intron_variant	Intron 5 of 11		NP_955472.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSPD1	ENST00000388968.8	c.607-53C>G		intron_variant	Intron 5 of 11	1	NM_002156.5	ENSP00000373620.3

Frequencies

GnomAD3 genomes AF: 0.139 AC: 21174 AN: 151902 Hom.: 1838 Cov.: 32

Gnomad AFR AF: 0.0363

Gnomad AMI AF: 0.196

Gnomad AMR AF: 0.184

Gnomad ASJ AF: 0.232

Gnomad EAS AF: 0.231

Gnomad SAS AF: 0.0938

Gnomad FIN AF: 0.179

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.175

Gnomad OTH AF: 0.170

GnomAD4 exome AF: 0.168 AC: 125482 AN: 747408 Hom.: 11288 Cov.: 10 AF XY: 0.166 AC XY: 66128 AN XY: 399194

African (AFR) AF: 0.0323 AC: 645 AN: 19964

American (AMR) AF: 0.186 AC: 8048 AN: 43340

Ashkenazi Jewish (ASJ) AF: 0.230 AC: 4953 AN: 21528

East Asian (EAS) AF: 0.231 AC: 8413 AN: 36396

South Asian (SAS) AF: 0.0928 AC: 6641 AN: 71574

European-Finnish (FIN) AF: 0.178 AC: 9354 AN: 52664

Middle Eastern (MID) AF: 0.217 AC: 946 AN: 4352

European-Non Finnish (NFE) AF: 0.174 AC: 80178 AN: 460670

Other (OTH) AF: 0.171 AC: 6304 AN: 36920

GnomAD4 genome AF: 0.139 AC: 21181 AN: 152020 Hom.: 1841 Cov.: 32 AF XY: 0.141 AC XY: 10481 AN XY: 74300

African (AFR) AF: 0.0363 AC: 1505 AN: 41494

American (AMR) AF: 0.184 AC: 2805 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.232 AC: 807 AN: 3472

East Asian (EAS) AF: 0.232 AC: 1202 AN: 5174

South Asian (SAS) AF: 0.0955 AC: 460 AN: 4816

European-Finnish (FIN) AF: 0.179 AC: 1890 AN: 10544

Middle Eastern (MID) AF: 0.272 AC: 80 AN: 294

European-Non Finnish (NFE) AF: 0.175 AC: 11898 AN: 67944

Other (OTH) AF: 0.169 AC: 356 AN: 2108

Alfa AF: 0.145 Hom.: 220

Bravo AF: 0.140

Asia WGS AF: 0.137 AC: 477 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 18, 2018

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. -

-

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
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.055
DANN	Benign	0.61
PhyloP100		-1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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: rs7585486; hg19: chr2-198359027; COSMIC: COSV61444608; COSMIC: COSV61444608;