13-100368513-C-T

Variant names:

• chr13-100368513-C-T
• rs202247816
• NM_000282.4:c.1685C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000282.4(PCCA):​c.1685C>T​(p.Ser562Leu) 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 1,459,100 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PCCA NM_000282.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.58
• Publications: 0 publications found

Genes affected

PCCA (HGNC:8653): (propionyl-CoA carboxylase subunit alpha) The protein encoded by this gene is the alpha subunit of the heterodimeric mitochondrial enzyme Propionyl-CoA carboxylase. PCCA encodes the biotin-binding region of this enzyme. Mutations in either PCCA or PCCB (encoding the beta subunit) lead to an enzyme deficiency resulting in propionic acidemia. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, May 2010]

PCCA Gene-Disease associations (from GenCC):

• propionic acidemia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, ClinGen, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2675602).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCCA	NM_000282.4	c.1685C>T	p.Ser562Leu	missense_variant	Exon 19 of 24	ENST00000376285.6	NP_000273.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCCA	ENST00000376285.6	c.1685C>T	p.Ser562Leu	missense_variant	Exon 19 of 24	1	NM_000282.4	ENSP00000365462.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459100 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 726028

African (AFR) AF: 0.00 AC: 0 AN: 33416

American (AMR) AF: 0.00 AC: 0 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39564

South Asian (SAS) AF: 0.00 AC: 0 AN: 86122

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109742

Other (OTH) AF: 0.00 AC: 0 AN: 60288

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Uncertain	0.052	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	.;.;T;T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.27	T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.2	.;M;M;.
PhyloP100		3.6
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.2	N;N;N;N
REVEL	Uncertain	0.38
Sift	Benign	0.31	T;T;T;T
Sift4G	Benign	0.24	T;T;T;D
Polyphen		0.022	B;.;B;.
Vest4		0.80
MutPred		0.38		.;Gain of ubiquitination at K564 (P = 0.1283);Gain of ubiquitination at K564 (P = 0.1283);.;
MVP		0.75
MPC		0.13
ClinPred		0.48	T
GERP RS		3.9
PromoterAI		-0.017	Neutral
Varity_R		0.089
gMVP		0.64
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

dbSNP: rs202247816; hg19: chr13-101020767; COSMIC: COSV66189217;