3-119660015-C-T

Variant names:

• chr3-119660015-C-T
• NM_001369919.2:c.409G>A

Variant summary

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

The NM_001369919.2(POPDC2):​c.409G>A​(p.Val137Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: POPDC2 NM_001369919.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.05
• Publications: 0 publications found

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]

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=0.21344897).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001369919.2. 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
	POPDC2	NM_001369919.2	MANE Select	c.409G>A	p.Val137Ile	missense	Exon 1 of 4	NP_001356848.1	C9J3P7
	POPDC2	NM_022135.4		c.409G>A	p.Val137Ile	missense	Exon 1 of 4	NP_071418.2
	POPDC2	NM_001308333.2		c.409G>A	p.Val137Ile	missense	Exon 1 of 5	NP_001295262.1	Q9HBU9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POPDC2	ENST00000493094.6	TSL:5 MANE Select	c.409G>A	p.Val137Ile	missense	Exon 1 of 4	ENSP00000417250.1	C9J3P7
	POPDC2	ENST00000264231.7	TSL:1	c.409G>A	p.Val137Ile	missense	Exon 1 of 4	ENSP00000264231.3	Q9HBU9-1
	POPDC2	ENST00000468801.1	TSL:1	c.409G>A	p.Val137Ile	missense	Exon 1 of 5	ENSP00000420715.1	Q9HBU9-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461842 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727214

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111968

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.012	T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
PhyloP100		5.1
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.22
Sift	Benign	0.29	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.11
MutPred		0.55		Gain of helix (P = 0.132)
MVP		0.32
MPC		0.17
ClinPred		0.82	D
GERP RS		5.8
Varity_R		0.093
gMVP		0.21
Mutation Taster		=78/22	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

hg19: chr3-119378862;