Genetic Variant GRPEL2:p.Ile84Leu (chr5-149349672-A-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_152407.4(GRPEL2):c.250A>C(p.Ile84Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,484 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I84V) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

GRPEL2
NM_152407.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.213

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

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 (MetaRNN=0.047487557).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152407.4. 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
	GRPEL2	NM_152407.4	MANE Select	c.250A>C	p.Ile84Leu	missense	Exon 3 of 4	NP_689620.2
	GRPEL2-AS1	NR_132366.1		n.119-1274T>G		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GRPEL2	ENST00000329271.8	TSL:1 MANE Select	c.250A>C	p.Ile84Leu	missense	Exon 3 of 4	ENSP00000329558.3	Q8TAA5-1
GRPEL2	ENST00000913747.1		c.229A>C	p.Ile77Leu	missense	Exon 3 of 4	ENSP00000583806.1
GRPEL2	ENST00000513661.5	TSL:2	c.250A>C	p.Ile84Leu	missense	Exon 3 of 3	ENSP00000426331.1	D6RGI6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460484

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726604

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33420

American (AMR)

AF:

0.00

AC:

AN:

44644

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39664

South Asian (SAS)

AF:

0.00

AC:

AN:

86182

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1110952

Other (OTH)

AF:

0.00

AC:

AN:

60328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.65

CADD

Benign

8.7

(source)

DANN

Benign

0.72

DEOGEN2

Benign

0.019

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.15

M_CAP

Benign

0.0044

MetaRNN

Benign

0.047

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-1.6

PhyloP100

-0.21

PrimateAI

Benign

0.34

PROVEAN

Benign

0.67

REVEL

Benign

0.045

Sift

Benign

1.0

Sift4G

Benign

0.77

Polyphen

0.0

Vest4

0.14

MutPred

0.64

Loss of MoRF binding (P = 0.1194)

MVP

0.29

MPC

0.22

ClinPred

0.048

GERP RS

-0.54

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.044

gMVP

0.21

Mutation Taster

=89/11

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over