Genetic Variant PTCD2:p.Arg105Trp (chr5-72326704-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001284404.2(PTCD2):c.-7C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000352 in 1,614,146 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00036 ( 1 hom. )

Consequence

PTCD2
NM_001284404.2 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.800

Variant links:

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]

PTCD2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05829692).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTCD2	NM_024754.5 link	c.313C>T	p.Arg105Trp	missense_variant	Exon 3 of 10	ENST00000380639.10	NP_079030.3	Q8WV60-1A0A024RAM6B3KPU6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTCD2	ENST00000380639.10 link	c.313C>T	p.Arg105Trp	missense_variant	Exon 3 of 10	5	NM_024754.5	ENSP00000370013.4		Q8WV60-1

Frequencies

GnomAD3 genomes

AF:

0.000256

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000785

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000228

AC:

AN:

249518

Hom.:

AF XY:

0.000192

AC XY:

AN XY:

135370

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.000203

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.0000556

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000389

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000362

AC:

529

AN:

1461832

Hom.:

Cov.:

AF XY:

0.000349

AC XY:

254

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000335

Gnomad4 ASJ exome

AF:

0.000344

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.000429

Gnomad4 OTH exome

AF:

0.000364

GnomAD4 genome

AF:

0.000256

AC:

AN:

152314

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.000784

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000279

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000343

Hom.:

Bravo

AF:

0.000321

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000520

AC:

ESP6500EA

AF:

0.000364

AC:

ExAC

AF:

0.000248

AC:

EpiCase

AF:

0.000763

EpiControl

AF:

0.000474

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.313C>T (p.R105W) alteration is located in exon 3 (coding exon 3) of the PTCD2 gene. This alteration results from a C to T substitution at nucleotide position 313, causing the arginine (R) at amino acid position 105 to be replaced by a tryptophan (W). 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

0.11

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.50

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.070

M_CAP

Benign

0.011

MetaRNN

Benign

0.058

MetaSVM

Benign

-0.95

MutationAssessor

Uncertain

2.5

PrimateAI

Benign

0.24

PROVEAN

Uncertain

-2.7

REVEL

Benign

0.081

Sift

Uncertain

0.019

Sift4G

Uncertain

0.020

Polyphen

0.038

Vest4

0.21

MVP

0.32

MPC

0.14

ClinPred

0.045

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.093

gMVP

0.42

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.20

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.20

Position offset: 37

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over