rs41265953

Variant names:

• chr2-197487080-C-G
• rs41265953
• NM_002156.5:c.1688G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 6.98
• Publications: 13 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]

SNORA105B (HGNC:51398): (small nucleolar RNA, H/ACA box 105B)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 137563.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 26 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.1688G>C	p.Gly563Ala	missense	Exon 12 of 12	NP_002147.2
	HSPD1	NM_199440.2		c.1688G>C	p.Gly563Ala	missense	Exon 12 of 12	NP_955472.1	A0A024R3X4
	SNORA105B	NR_132788.1		n.-177G>C		upstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPD1	ENST00000388968.8	TSL:1 MANE Select	c.1688G>C	p.Gly563Ala	missense	Exon 12 of 12	ENSP00000373620.3	P10809-1
	HSPD1	ENST00000954440.1		c.1736G>C	p.Gly579Ala	missense	Exon 12 of 12	ENSP00000624499.1
	HSPD1	ENST00000345042.6	TSL:5	c.1688G>C	p.Gly563Ala	missense	Exon 12 of 12	ENSP00000340019.2	P10809-1

Frequencies

GnomAD3 genomes AF: 0.0158 AC: 2396 AN: 152086 Hom.: 26 Cov.: 32

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

GnomAD2 exomes AF: 0.0167 AC: 4126 AN: 246966 AF XY: 0.0175

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 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.: 22 AF XY: 0.0196 AC XY: 13521 AN XY: 688938

African (AFR) AF: 0.00275 AC: 87 AN: 31648

American (AMR) AF: 0.00734 AC: 327 AN: 44550

Ashkenazi Jewish (ASJ) AF: 0.0160 AC: 409 AN: 25608

East Asian (EAS) AF: 0.000102 AC: 4 AN: 39300

South Asian (SAS) AF: 0.0114 AC: 961 AN: 84564

European-Finnish (FIN) AF: 0.0476 AC: 2540 AN: 53370

Middle Eastern (MID) AF: 0.00609 AC: 34 AN: 5586

European-Non Finnish (NFE) AF: 0.0213 AC: 21972 AN: 1032672

Other (OTH) AF: 0.0191 AC: 1097 AN: 57452

GnomAD4 genome AF: 0.0157 AC: 2397 AN: 152204 Hom.: 26 Cov.: 32 AF XY: 0.0167 AC XY: 1242 AN XY: 74422

African (AFR) AF: 0.00289 AC: 120 AN: 41546

American (AMR) AF: 0.0119 AC: 182 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0156 AC: 54 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00870 AC: 42 AN: 4830

European-Finnish (FIN) AF: 0.0499 AC: 528 AN: 10590

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

European-Non Finnish (NFE) AF: 0.0210 AC: 1429 AN: 67990

Other (OTH) AF: 0.0166 AC: 35 AN: 2114

Alfa AF: 0.0174 Hom.: 6

Bravo AF: 0.0129

ESP6500AA AF: 0.00305 AC: 13

ESP6500EA AF: 0.0169 AC: 142

ExAC AF: 0.0161 AC: 1943

EpiCase AF: 0.0190

EpiControl AF: 0.0175

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.83	D
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.0087	T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		7.0
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-4.1	D
REVEL	Uncertain	0.55
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.015	D
Polyphen		1.0	D
Vest4		0.20
MPC		2.0
ClinPred		0.030	T
GERP RS		5.2
Varity_R		0.73
gMVP		0.76
Mutation Taster		=67/33	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: rs41265953; hg19: chr2-198351804; COSMIC: COSV61445925; COSMIC: COSV61445925;