rs146525523

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001369919.2(POPDC2):​c.299G>C​(p.Arg100Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R100H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

POPDC2
NM_001369919.2 missense

Scores

3
9
7

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.26
Variant links:
Genes affected
POPDC2 (HGNC:17648): (popeye domain containing 2) This gene encodes a member of the POP family of proteins which contain three putative transmembrane domains. This membrane associated protein is predominantly expressed in skeletal and cardiac muscle, and may have an important function in these tissues. [provided by RefSeq, Jul 2008]
COX17 (HGNC:2264): (cytochrome c oxidase copper chaperone COX17) Cytochrome c oxidase (COX), the terminal component of the mitochondrial respiratory chain, catalyzes the electron transfer from reduced cytochrome c to oxygen. This component is a heteromeric complex consisting of 3 catalytic subunits encoded by mitochondrial genes and multiple structural subunits encoded by nuclear genes. The mitochondrially-encoded subunits function in electron transfer, and the nuclear-encoded subunits may function in the regulation and assembly of the complex. This nuclear gene encodes a protein which is not a structural subunit, but may be involved in the recruitment of copper to mitochondria for incorporation into the COX apoenzyme. This protein shares 92% amino acid sequence identity with mouse and rat Cox17 proteins. This gene is no longer considered to be a candidate gene for COX deficiency. A pseudogene COX17P has been found on chromosome 13. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.943

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
POPDC2NM_001369919.2 linkc.299G>C p.Arg100Pro missense_variant Exon 1 of 4 ENST00000493094.6 NP_001356848.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
POPDC2ENST00000493094.6 linkc.299G>C p.Arg100Pro missense_variant Exon 1 of 4 5 NM_001369919.2 ENSP00000417250.1 C9J3P7

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251380
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135850
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:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461876
Hom.:
0
Cov.:
59
AF XY:
0.00000138
AC XY:
1
AN XY:
727242
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:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.51
BayesDel_addAF
Benign
-0.030
T
BayesDel_noAF
Benign
-0.18
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.24
T;.;.
Eigen
Uncertain
0.46
Eigen_PC
Uncertain
0.33
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Uncertain
0.90
D;D;D
M_CAP
Benign
0.049
D
MetaRNN
Pathogenic
0.94
D;D;D
MetaSVM
Benign
-0.74
T
MutationAssessor
Pathogenic
3.1
M;.;M
PrimateAI
Benign
0.27
T
PROVEAN
Pathogenic
-6.0
D;D;D
REVEL
Uncertain
0.32
Sift
Uncertain
0.0020
D;D;D
Sift4G
Uncertain
0.0080
D;D;D
Polyphen
1.0
D;.;D
Vest4
0.73
MutPred
0.73
Loss of methylation at R98 (P = 0.0513);Loss of methylation at R98 (P = 0.0513);Loss of methylation at R98 (P = 0.0513);
MVP
0.41
MPC
0.41
ClinPred
0.98
D
GERP RS
3.9
Varity_R
0.69
gMVP
0.81

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.

Other links and lift over

dbSNP: rs146525523; hg19: chr3-119378972; API