2-197498705-G-A

Variant names:

• chr2-197498705-G-A
• rs11551346
• NM_002156.5:c.144C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_002156.5(HSPD1):​c.144C>T​(p.Ala48Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00426 in 1,613,872 control chromosomes in the GnomAD database, including 199 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (121 hom., cov: 33)
  • Exomes 𝑓: 0.0023 (78 hom.)
• Consequence: HSPD1 NM_002156.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.29
• Publications: 1 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 2-197498705-G-A is Benign according to our data. Variant chr2-197498705-G-A is described in ClinVar as Benign. ClinVar VariationId is 137565.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.29 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0781 is higher than 0.05.

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.144C>T	p.Ala48Ala	synonymous	Exon 2 of 12	NP_002147.2
	HSPD1	NM_199440.2		c.144C>T	p.Ala48Ala	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.144C>T	p.Ala48Ala	synonymous	Exon 2 of 12	ENSP00000373620.3	P10809-1
	HSPD1	ENST00000954440.1		c.144C>T	p.Ala48Ala	synonymous	Exon 2 of 12	ENSP00000624499.1
	HSPD1	ENST00000345042.6	TSL:5	c.144C>T	p.Ala48Ala	synonymous	Exon 2 of 12	ENSP00000340019.2	P10809-1

Frequencies

GnomAD3 genomes AF: 0.0228 AC: 3460 AN: 152004 Hom.: 121 Cov.: 33

Gnomad AFR AF: 0.0804

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00498

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.0181

GnomAD2 exomes AF: 0.00595 AC: 1496 AN: 251450 AF XY: 0.00425

Gnomad AFR exome AF: 0.0839

Gnomad AMR exome AF: 0.00292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000158

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00233 AC: 3402 AN: 1461750 Hom.: 78 Cov.: 33 AF XY: 0.00197 AC XY: 1432 AN XY: 727178

African (AFR) AF: 0.0825 AC: 2757 AN: 33420

American (AMR) AF: 0.00347 AC: 155 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.000174 AC: 15 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00226 AC: 13 AN: 5762

European-Non Finnish (NFE) AF: 0.000127 AC: 141 AN: 1111976

Other (OTH) AF: 0.00532 AC: 321 AN: 60374

GnomAD4 genome AF: 0.0228 AC: 3469 AN: 152122 Hom.: 121 Cov.: 33 AF XY: 0.0221 AC XY: 1641 AN XY: 74376

African (AFR) AF: 0.0804 AC: 3335 AN: 41466

American (AMR) AF: 0.00491 AC: 75 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68000

Other (OTH) AF: 0.0180 AC: 38 AN: 2116

Alfa AF: 0.00416 Hom.: 14

Bravo AF: 0.0265

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	Hereditary spastic paraplegia 13 (1)
-	-	1	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	9.1
DANN	Benign	0.90
PhyloP100		-1.3
Mutation Taster		=96/4	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: rs11551346; hg19: chr2-198363429; COSMIC: COSV52099637; COSMIC: COSV52099637;