rs768750176

Variant names:

• chr13-100111859-G-A
• rs768750176
• NM_000282.4:c.202G>A

Your query was ambiguous. Multiple possible variants found:

• chr13-100111859-G-A
• chr13-100111859-G-T
• chr13-100111859-G-C

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_000282.4(PCCA):​c.202G>A​(p.Val68Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000497 in 1,609,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V68F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: PCCA NM_000282.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.0490
• 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: Myriad Women’s Health, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, G2P

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0933356).
• BP6: Variant 13-100111859-G-A is Benign according to our data. Variant chr13-100111859-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 568000.

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.202G>A	p.Val68Ile	missense	Exon 3 of 24	NP_000273.2	P05165-1
	PCCA	NM_001352605.2		c.202G>A	p.Val68Ile	missense	Exon 3 of 23	NP_001339534.1
	PCCA	NM_001127692.3		c.124G>A	p.Val42Ile	missense	Exon 2 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.202G>A	p.Val68Ile	missense	Exon 3 of 24	ENSP00000365462.1	P05165-1
	PCCA	ENST00000881637.1		c.202G>A	p.Val68Ile	missense	Exon 3 of 25	ENSP00000551696.1
	PCCA	ENST00000881640.1		c.202G>A	p.Val68Ile	missense	Exon 3 of 25	ENSP00000551699.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152036 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000412 AC: 6 AN: 1457036 Hom.: 0 Cov.: 29 AF XY: 0.00000276 AC XY: 2 AN XY: 725106

African (AFR) AF: 0.00 AC: 0 AN: 33354

American (AMR) AF: 0.00 AC: 0 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26074

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39556

South Asian (SAS) AF: 0.00 AC: 0 AN: 86050

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53372

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5368

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108416

Other (OTH) AF: 0.0000831 AC: 5 AN: 60180

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152036 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74250

African (AFR) AF: 0.00 AC: 0 AN: 41402

American (AMR) AF: 0.0000655 AC: 1 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10562

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

Asia WGS AF: 0.00434 AC: 15 AN: 3466

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	Propionic acidemia (2)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.031	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	0.40
DANN	Benign	0.53
DEOGEN2	Uncertain	0.56	D
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.093	T
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	-0.72	N
PhyloP100		0.049
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.51	N
REVEL	Uncertain	0.34
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.17
MutPred		0.58		Gain of methylation at K65 (P = 0.1032)
MVP		0.52
MPC		0.11
ClinPred		0.014	T
GERP RS		-7.7
Varity_R		0.018
gMVP		0.27
Mutation Taster		=96/4	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: rs768750176; hg19: chr13-100764113;