rs202049874

Variant names:

• chr13-100111903-C-T
• rs202049874
• NM_000282.4:c.231+15C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000282.4(PCCA):​c.231+15C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00272 in 1,606,098 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0028 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (19 hom.)
• Consequence: PCCA NM_000282.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.224
• Publications: 1 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 13-100111903-C-T is Benign according to our data. Variant chr13-100111903-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 310842.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00275 (418/151918) while in subpopulation NFE AF = 0.00244 (166/67944). AF 95% confidence interval is 0.00214. There are 2 homozygotes in GnomAd4. There are 261 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

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.231+15C>T		intron	N/A	NP_000273.2
	PCCA	NM_001352605.2		c.231+15C>T		intron	N/A	NP_001339534.1
	PCCA	NM_001127692.3		c.153+15C>T		intron	N/A	NP_001121164.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCCA	ENST00000376285.6	TSL:1 MANE Select	c.231+15C>T		intron	N/A	ENSP00000365462.1
	PCCA	ENST00000881637.1		c.231+15C>T		intron	N/A	ENSP00000551696.1
	PCCA	ENST00000881640.1		c.231+15C>T		intron	N/A	ENSP00000551699.1

Frequencies

GnomAD3 genomes AF: 0.00275 AC: 418 AN: 151802 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000339

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000723

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.0208

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00244

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00310 AC: 776 AN: 250160 AF XY: 0.00299

Gnomad AFR exome AF: 0.000186

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0212

Gnomad NFE exome AF: 0.00254

Gnomad OTH exome AF: 0.00197

GnomAD4 exome AF: 0.00271 AC: 3946 AN: 1454180 Hom.: 19 Cov.: 29 AF XY: 0.00266 AC XY: 1922 AN XY: 723856

African (AFR) AF: 0.000390 AC: 13 AN: 33324

American (AMR) AF: 0.000448 AC: 20 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26076

East Asian (EAS) AF: 0.0000506 AC: 2 AN: 39520

South Asian (SAS) AF: 0.000256 AC: 22 AN: 85998

European-Finnish (FIN) AF: 0.0221 AC: 1177 AN: 53360

Middle Eastern (MID) AF: 0.000364 AC: 2 AN: 5498

European-Non Finnish (NFE) AF: 0.00234 AC: 2582 AN: 1105644

Other (OTH) AF: 0.00213 AC: 128 AN: 60090

GnomAD4 genome AF: 0.00275 AC: 418 AN: 151918 Hom.: 2 Cov.: 32 AF XY: 0.00352 AC XY: 261 AN XY: 74250

African (AFR) AF: 0.000338 AC: 14 AN: 41436

American (AMR) AF: 0.000722 AC: 11 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000209 AC: 1 AN: 4790

European-Finnish (FIN) AF: 0.0208 AC: 220 AN: 10558

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00244 AC: 166 AN: 67944

Other (OTH) AF: 0.00284 AC: 6 AN: 2110

Alfa AF: 0.00255 Hom.: 0

Bravo AF: 0.00112

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	1	1	Propionic acidemia (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.1
DANN	Benign	0.57
PhyloP100		0.22
Mutation Taster		=100/0	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: rs202049874; hg19: chr13-100764157;