2-197501064-C-T

Variant names:

• chr2-197501064-C-T
• rs2305560
• NM_002157.3:c.4-10C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002157.3(HSPE1):​c.4-10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.17 in 1,602,078 control chromosomes in the GnomAD database, including 24,327 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.15 (1897 hom., cov: 32)
  • Exomes 𝑓: 0.17 (22430 hom.)
• Consequence: HSPE1 NM_002157.3 intron
• Scores: Splicing: ADA: 0.00008184
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.316
• Publications: 12 publications found

Genes affected

HSPE1 (HGNC:5269): (heat shock protein family E (Hsp10) member 1) This gene encodes a major heat shock protein which functions as a chaperonin. Its structure consists of a heptameric ring which binds to another heat shock protein in order to form a symmetric, functional heterodimer which enhances protein folding in an ATP-dependent manner. This gene and its co-chaperonin, HSPD1, are arranged in a head-to-head orientation on chromosome 2. Naturally occurring read-through transcription occurs between this locus and the neighboring locus MOBKL3.[provided by RefSeq, Feb 2011]

HSPE1-MOB4 (HGNC:49184): (HSPE1-MOB4 readthrough) This locus represents naturally occurring read-through transcription between the neighboring HSPE1 (heat shock 10kDa protein 1 (chaperonin 10)) and MOB4 (MOB family member 4, phocein) genes on chromosome 2. The read-through transcript produces a fusion protein that shares sequence identity with each individual gene product. [provided by RefSeq, Oct 2011]

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.219 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPE1	NM_002157.3	c.4-10C>T		intron_variant	Intron 1 of 3	ENST00000233893.10	NP_002148.1
HSPE1-MOB4	NM_001202485.2	c.4-10C>T		intron_variant	Intron 1 of 8		NP_001189414.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSPE1	ENST00000233893.10	c.4-10C>T		intron_variant	Intron 1 of 3	1	NM_002157.3	ENSP00000233893.5
HSPE1-MOB4	ENST00000604458.1	c.4-10C>T		intron_variant	Intron 1 of 8	3		ENSP00000474534.1

Frequencies

GnomAD3 genomes AF: 0.146 AC: 22251 AN: 152074 Hom.: 1894 Cov.: 32

Gnomad AFR AF: 0.0613

Gnomad AMI AF: 0.195

Gnomad AMR AF: 0.186

Gnomad ASJ AF: 0.235

Gnomad EAS AF: 0.229

Gnomad SAS AF: 0.0925

Gnomad FIN AF: 0.178

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.175

Gnomad OTH AF: 0.174

GnomAD2 exomes AF: 0.167 AC: 41013 AN: 246078 AF XY: 0.167

Gnomad AFR exome AF: 0.0572

Gnomad AMR exome AF: 0.190

Gnomad ASJ exome AF: 0.232

Gnomad EAS exome AF: 0.234

Gnomad FIN exome AF: 0.177

Gnomad NFE exome AF: 0.175

Gnomad OTH exome AF: 0.196

GnomAD4 exome AF: 0.173 AC: 250308 AN: 1449886 Hom.: 22430 Cov.: 31 AF XY: 0.171 AC XY: 123415 AN XY: 720836

African (AFR) AF: 0.0541 AC: 1783 AN: 32940

American (AMR) AF: 0.189 AC: 8063 AN: 42682

Ashkenazi Jewish (ASJ) AF: 0.237 AC: 6068 AN: 25654

East Asian (EAS) AF: 0.229 AC: 9079 AN: 39636

South Asian (SAS) AF: 0.0925 AC: 7827 AN: 84586

European-Finnish (FIN) AF: 0.178 AC: 9483 AN: 53254

Middle Eastern (MID) AF: 0.220 AC: 1255 AN: 5712

European-Non Finnish (NFE) AF: 0.178 AC: 196445 AN: 1105548

Other (OTH) AF: 0.172 AC: 10305 AN: 59874

GnomAD4 genome AF: 0.146 AC: 22262 AN: 152192 Hom.: 1897 Cov.: 32 AF XY: 0.148 AC XY: 10979 AN XY: 74396

African (AFR) AF: 0.0612 AC: 2545 AN: 41562

American (AMR) AF: 0.186 AC: 2845 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.235 AC: 813 AN: 3466

East Asian (EAS) AF: 0.230 AC: 1192 AN: 5180

South Asian (SAS) AF: 0.0943 AC: 454 AN: 4816

European-Finnish (FIN) AF: 0.178 AC: 1883 AN: 10590

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

European-Non Finnish (NFE) AF: 0.175 AC: 11907 AN: 67972

Other (OTH) AF: 0.173 AC: 366 AN: 2112

Alfa AF: 0.161 Hom.: 1163

Bravo AF: 0.148

Asia WGS AF: 0.138 AC: 481 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	6.7
DANN	Benign	0.86
PhyloP100		-0.32
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000082
dbscSNV1_RF	Benign	0.0080
SpliceAI score (max)		0.040		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: rs2305560; hg19: chr2-198365788; COSMIC: COSV52098936; COSMIC: COSV52098936;