rs189395138

Variant names:

• chr2-197488500-G-A
• rs189395138
• NM_002156.5:c.1216-9C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_002156.5(HSPD1):​c.1216-9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00263 in 1,611,940 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0026 (13 hom.)
• Consequence: HSPD1 NM_002156.5 intron
• Scores: Splicing: ADA: 0.000009175
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.965
• Publications: 0 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• hypomyelinating leukodystrophy 4

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 2-197488500-G-A is Benign according to our data. Variant chr2-197488500-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 137562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 5 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.1216-9C>T		intron	N/A	NP_002147.2
	HSPD1	NM_199440.2		c.1216-9C>T		intron	N/A	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.1216-9C>T		intron	N/A	ENSP00000373620.3	P10809-1
	HSPD1	ENST00000954440.1		c.1264-9C>T		intron	N/A	ENSP00000624499.1
	HSPD1	ENST00000345042.6	TSL:5	c.1216-9C>T		intron	N/A	ENSP00000340019.2	P10809-1

Frequencies

GnomAD3 genomes AF: 0.00339 AC: 516 AN: 152116 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0163

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00471

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00323 AC: 811 AN: 250704 AF XY: 0.00313

Gnomad AFR exome AF: 0.000310

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00477

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0149

Gnomad NFE exome AF: 0.00357

Gnomad OTH exome AF: 0.00441

GnomAD4 exome AF: 0.00255 AC: 3729 AN: 1459706 Hom.: 13 Cov.: 30 AF XY: 0.00255 AC XY: 1854 AN XY: 726382

African (AFR) AF: 0.000150 AC: 5 AN: 33438

American (AMR) AF: 0.0000894 AC: 4 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00486 AC: 127 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86204

European-Finnish (FIN) AF: 0.0145 AC: 774 AN: 53416

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 0.00242 AC: 2683 AN: 1110028

Other (OTH) AF: 0.00222 AC: 134 AN: 60310

GnomAD4 genome AF: 0.00339 AC: 516 AN: 152234 Hom.: 5 Cov.: 33 AF XY: 0.00398 AC XY: 296 AN XY: 74438

African (AFR) AF: 0.000193 AC: 8 AN: 41546

American (AMR) AF: 0.0000654 AC: 1 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4816

European-Finnish (FIN) AF: 0.0163 AC: 173 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00471 AC: 320 AN: 67994

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00497 Hom.: 3

Bravo AF: 0.00133

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	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
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.5
DANN	Benign	0.38
PhyloP100		-0.96
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000092
dbscSNV1_RF	Benign	0.018
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs189395138;

hg19: chr2-198353224;