NM_000282.4:c.1685C>G

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_000282.4(PCCA):​c.1685C>G​(p.Ser562*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as not provided (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PCCA NM_000282.4 stop_gained
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 3.58
• Publications: 5 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: Myriad Women’s Health, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, G2P

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000282.4. 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
	PCCA	NM_000282.4	MANE Select	c.1685C>G	p.Ser562*	stop_gained	Exon 19 of 24	NP_000273.2	P05165-1
	PCCA	NM_001352605.2		c.1685C>G	p.Ser562*	stop_gained	Exon 19 of 23	NP_001339534.1
	PCCA	NM_001127692.3		c.1607C>G	p.Ser536*	stop_gained	Exon 18 of 23	NP_001121164.1	P05165-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCCA	ENST00000376285.6	TSL:1 MANE Select	c.1685C>G	p.Ser562*	stop_gained	Exon 19 of 24	ENSP00000365462.1	P05165-1
	PCCA	ENST00000881637.1		c.1808C>G	p.Ser603*	stop_gained	Exon 20 of 25	ENSP00000551696.1
	PCCA	ENST00000881640.1		c.1790C>G	p.Ser597*	stop_gained	Exon 20 of 25	ENSP00000551699.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: not provided

Revision: no classification provided

Pathogenic	VUS	Benign	Condition
-	-	-	Propionic acidemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	37
DANN	Uncertain	0.98
Eigen	Uncertain	0.45
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.78	D
PhyloP100		3.6
Vest4		0.89
GERP RS		3.9
PromoterAI		-0.0088	Neutral
Mutation Taster		=2/198	disease causing (ClinVar)

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

dbSNP: rs202247816; hg19: chr13-101020767; COSMIC: COSV66194414;