5-72338659-G-A

Variant names:

• chr5-72338659-G-A
• rs768099899
• NM_024754.5:c.677G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024754.5(PTCD2):​c.677G>A​(p.Arg226Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,459,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PTCD2 NM_024754.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.89

Genes affected

PTCD2 (HGNC:25734): (pentatricopeptide repeat domain 2) Enables RNA binding activity. Predicted to be involved in mitochondrion organization and regulation of mRNA processing. Predicted to act upstream of or within animal organ development; muscle cell development; and regulation of gene expression. Located in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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=0.16064608).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTCD2	NM_024754.5	c.677G>A	p.Arg226Lys	missense_variant	Exon 7 of 10	ENST00000380639.10	NP_079030.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTCD2	ENST00000380639.10	c.677G>A	p.Arg226Lys	missense_variant	Exon 7 of 10	5	NM_024754.5	ENSP00000370013.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1459890 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 726454

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.677G>A (p.R226K) alteration is located in exon 7 (coding exon 7) of the PTCD2 gene. This alteration results from a G to A substitution at nucleotide position 677, causing the arginine (R) at amino acid position 226 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	0.14
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.026	.;T;T;.;.
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.083
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.78	T;T;.;T;T
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.16	T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.7	.;.;M;.;.
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.79	N;.;N;N;N
REVEL	Benign	0.087
Sift	Benign	0.064	T;.;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T
Polyphen		0.016	.;.;B;.;.
Vest4		0.45
MutPred		0.43		.;.;Gain of ubiquitination at R226 (P = 0.03);.;.;
MVP		0.32
MPC		0.20
ClinPred		0.42	T
GERP RS		3.0
Varity_R		0.13
gMVP		0.61

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

Publications

LitVar

Other links and lift over

dbSNP: rs768099899; hg19: chr5-71634486;