5-149348393-G-C

Variant names:

• chr5-149348393-G-C
• rs758926660
• NM_152407.4:c.199G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152407.4(GRPEL2):​c.199G>C​(p.Val67Leu) 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 1,458,930 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. V67I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GRPEL2 NM_152407.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.45
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08115816).

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.199G>C	p.Val67Leu	missense	Exon 2 of 4	NP_689620.2
	GRPEL2-AS1	NR_132366.1		n.124C>G		non_coding_transcript_exon	Exon 2 of 2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRPEL2	ENST00000329271.8	TSL:1 MANE Select	c.199G>C	p.Val67Leu	missense	Exon 2 of 4	ENSP00000329558.3	Q8TAA5-1
	GRPEL2	ENST00000913747.1		c.178G>C	p.Val60Leu	missense	Exon 2 of 4	ENSP00000583806.1
	GRPEL2	ENST00000513661.5	TSL:2	c.199G>C	p.Val67Leu	missense	Exon 2 of 3	ENSP00000426331.1	D6RGI6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1458930 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 725664

African (AFR) AF: 0.00 AC: 0 AN: 33298

American (AMR) AF: 0.00 AC: 0 AN: 43972

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26054

East Asian (EAS) AF: 0.00 AC: 0 AN: 39606

South Asian (SAS) AF: 0.00 AC: 0 AN: 85536

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5586

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111214

Other (OTH) AF: 0.0000166 AC: 1 AN: 60274

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	17
DANN	Benign	0.93
DEOGEN2	Benign	0.027	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.081	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.10	N
PhyloP100		1.4
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.032
Sift	Benign	0.13	T
Sift4G	Benign	0.15	T
Polyphen		0.015	B
Vest4		0.15
MutPred		0.49		Gain of ubiquitination at K65 (P = 0.0797)
MVP		0.36
MPC		0.22
ClinPred		0.076	T
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.031
gMVP		0.17
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs758926660; hg19: chr5-148727956;