Genetic Variant GRPEL2:p.Arg82Lys (chr5-149349667-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_152407.4(GRPEL2):c.245G>A(p.Arg82Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00014 in 1,609,286 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

GRPEL2
NM_152407.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.59

Variant links:

Genes affected

GRPEL2 (HGNC:21060): (GrpE like 2, mitochondrial) Predicted to enable adenyl-nucleotide exchange factor activity and unfolded protein binding activity. Predicted to be involved in protein import into mitochondrial matrix. Located in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

GRPEL2 links:

GRPEL2-AS1 (HGNC:48999): (GRPEL2 antisense RNA 1)

GRPEL2-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.16937128).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRPEL2	NM_152407.4 link	c.245G>A	p.Arg82Lys	missense_variant	Exon 3 of 4	ENST00000329271.8	NP_689620.2	Q8TAA5-1
GRPEL2-AS1	NR_132366.1 link	n.119-1269C>T		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRPEL2	ENST00000329271.8 link	c.245G>A	p.Arg82Lys	missense_variant	Exon 3 of 4	1	NM_152407.4	ENSP00000329558.3		Q8TAA5-1

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.000235

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000607

AC:

AN:

247136

Hom.:

AF XY:

0.0000748

AC XY:

AN XY:

133660

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000134

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000141

AC:

206

AN:

1457052

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

107

AN XY:

724956

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000177

Gnomad4 OTH exome

AF:

0.000150

GnomAD4 genome

AF:

0.000125

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74388

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000235

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000270

Hom.:

Bravo

AF:

0.0000945

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.000438

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 11, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.245G>A (p.R82K) alteration is located in exon 3 (coding exon 3) of the GRPEL2 gene. This alteration results from a G to A substitution at nucleotide position 245, causing the arginine (R) at amino acid position 82 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.44

.;T

Eigen

Benign

0.19

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.73

T;T

M_CAP

Benign

0.0064

MetaRNN

Benign

0.17

T;T

MetaSVM

Benign

-0.60

MutationAssessor

Uncertain

2.6

.;M

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-2.5

D;N

REVEL

Benign

0.17

Sift

Benign

0.052

T;D

Sift4G

Benign

0.19

T;T

Polyphen

0.10

.;B

Vest4

0.28

MVP

0.51

MPC

0.28

ClinPred

0.26

GERP RS

4.7

Varity_R

0.42

gMVP

0.53

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over