2-197500319-C-T

Variant names:

• chr2-197500319-C-T
• rs1116734
• ENST00000409729.1:c.-118C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000409729.1(HSPE1):​c.-118C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 151,778 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HSPE1 ENST00000409729.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.160
• Publications: 14 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]

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]

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]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPE1	NM_002157.3	c.-118C>T		upstream_gene_variant		ENST00000233893.10	NP_002148.1
HSPD1	NM_199440.2	c.-162G>A		upstream_gene_variant			NP_955472.1
HSPE1-MOB4	NM_001202485.2	c.-118C>T		upstream_gene_variant			NP_001189414.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSPE1	ENST00000233893.10	c.-118C>T		upstream_gene_variant		1	NM_002157.3	ENSP00000233893.5
HSPE1-MOB4	ENST00000604458.1	c.-118C>T		upstream_gene_variant		3		ENSP00000474534.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151778 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.42e-7 AC: 1 AN: 1347660 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 666976

African (AFR) AF: 0.0000327 AC: 1 AN: 30610

American (AMR) AF: 0.00 AC: 0 AN: 35402

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24746

East Asian (EAS) AF: 0.00 AC: 0 AN: 35584

South Asian (SAS) AF: 0.00 AC: 0 AN: 78090

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48348

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4202

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1034522

Other (OTH) AF: 0.00 AC: 0 AN: 56156

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151778 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74130

African (AFR) AF: 0.0000484 AC: 2 AN: 41364

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5100

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67854

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 1371

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	8.1
DANN	Benign	0.93
PhyloP100		-0.16
PromoterAI		-0.017	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs1116734; hg19: chr2-198365043;