NM_002156.5:c.1681A>G

Variant names:

• chr2-197487087-T-C
• rs371969794
• NM_002156.5:c.1681A>G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_002156.5(HSPD1):​c.1681A>G​(p.Met561Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000202 in 1,537,316 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (2 hom.)
• Consequence: HSPD1 NM_002156.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 7.45

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

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.027341574).
• BP6: Variant 2-197487087-T-C is Benign according to our data. Variant chr2-197487087-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 800207.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPD1	NM_002156.5	c.1681A>G	p.Met561Val	missense_variant	Exon 12 of 12	ENST00000388968.8	NP_002147.2
HSPD1	NM_199440.2	c.1681A>G	p.Met561Val	missense_variant	Exon 12 of 12		NP_955472.1
SNORA105B	NR_132788.1	n.-184A>G		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSPD1	ENST00000388968.8	c.1681A>G	p.Met561Val	missense_variant	Exon 12 of 12	1	NM_002156.5	ENSP00000373620.3

Frequencies

GnomAD3 genomes AF: 0.000362 AC: 55 AN: 152086 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000300 AC: 74 AN: 246852 Hom.: 1 AF XY: 0.000372 AC XY: 50 AN XY: 134490

Gnomad AFR exome AF: 0.00122

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000547

Gnomad SAS exome AF: 0.00163

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.0000360

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000186 AC: 257 AN: 1385112 Hom.: 2 Cov.: 22 AF XY: 0.000223 AC XY: 155 AN XY: 693614

Gnomad4 AFR exome AF: 0.00119

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000178

Gnomad4 SAS exome AF: 0.00179

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.0000422

Gnomad4 OTH exome AF: 0.000156

GnomAD4 genome AF: 0.000355 AC: 54 AN: 152204 Hom.: 0 Cov.: 32 AF XY: 0.000430 AC XY: 32 AN XY: 74424

Gnomad4 AFR AF: 0.00104

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000295

ESP6500AA AF: 0.000471 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000397 AC: 48

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spastic paraplegia Benign:1

Feb 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypomyelinating leukodystrophy 4 Benign:1

Nov 16, 2018

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Likely benign. The following ACMG criteria were applied in classifying this variant: BS1,BP4. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	0.010
CADD	Benign	20
DANN	Benign	0.94
DEOGEN2	Uncertain	0.78	D;D
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.81	.;T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.027	T;T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Pathogenic	3.3	M;M
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-2.2	N;N
REVEL	Uncertain	0.43
Sift	Benign	0.16	T;T
Sift4G	Uncertain	0.050	T;T
Polyphen		0.32	B;B
Vest4		0.58
MVP		0.58
MPC		1.9
ClinPred		0.13	T
GERP RS		5.2
Varity_R		0.31
gMVP		0.70

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

Publications

LitVar

Other links and lift over

dbSNP: rs371969794; hg19: chr2-198351811;