chr3-136250424-C-A

Variant names:

• chr3-136250424-C-A
• rs200185747
• NM_000532.5:c.49C>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS2

The NM_000532.5(PCCB):​c.49C>A​(p.Leu17Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00242 in 1,589,370 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L17L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0016 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0025 (3 hom.)
• Consequence: PCCB NM_000532.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: 0.372
• Publications: 9 publications found

Genes affected

PCCB (HGNC:8654): (propionyl-CoA carboxylase subunit beta) The protein encoded by this gene is a subunit of the propionyl-CoA carboxylase (PCC) enzyme, which is involved in the catabolism of propionyl-CoA. PCC is a mitochondrial enzyme that probably acts as a dodecamer of six alpha subunits and six beta subunits. This gene encodes the beta subunit of PCC. Defects in this gene are a cause of propionic acidemia type II (PA-2). Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, May 2010]

PCCB Gene-Disease associations (from GenCC):

• propionic acidemia

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

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 61 curated pathogenic missense variants (we use a threshold of 10). The gene has 6 curated benign missense variants. Gene score misZ: -0.86701 (below the threshold of 3.09). Trascript score misZ: -0.97134 (below the threshold of 3.09). GenCC associations: The gene is linked to propionic acidemia.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0063657463).
• BP6: Variant 3-136250424-C-A is Benign according to our data. Variant chr3-136250424-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 203883.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000532.5. 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
	PCCB	NM_000532.5	MANE Select	c.49C>A	p.Leu17Met	missense	Exon 1 of 15	NP_000523.2	P05166-1
	PCCB	NM_001178014.2		c.49C>A	p.Leu17Met	missense	Exon 1 of 16	NP_001171485.1	P05166-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCCB	ENST00000251654.9	TSL:1 MANE Select	c.49C>A	p.Leu17Met	missense	Exon 1 of 15	ENSP00000251654.4	P05166-1
	PCCB	ENST00000471595.5	TSL:1	c.49C>A	p.Leu17Met	missense	Exon 1 of 16	ENSP00000417549.1	E9PDR0
	PCCB	ENST00000478469.5	TSL:1	c.49C>A	p.Leu17Met	missense	Exon 1 of 9	ENSP00000420759.1	E7ENC1

Frequencies

GnomAD3 genomes AF: 0.00159 AC: 242 AN: 152270 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00295

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00153 AC: 313 AN: 204210 AF XY: 0.00151

Gnomad AFR exome AF: 0.000511

Gnomad AMR exome AF: 0.000496

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000842

Gnomad NFE exome AF: 0.00310

Gnomad OTH exome AF: 0.000983

GnomAD4 exome AF: 0.00250 AC: 3598 AN: 1436982 Hom.: 3 Cov.: 31 AF XY: 0.00236 AC XY: 1684 AN XY: 712736

African (AFR) AF: 0.000393 AC: 13 AN: 33052

American (AMR) AF: 0.000510 AC: 21 AN: 41204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25308

East Asian (EAS) AF: 0.00 AC: 0 AN: 38550

South Asian (SAS) AF: 0.00 AC: 0 AN: 83246

European-Finnish (FIN) AF: 0.000966 AC: 49 AN: 50738

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5690

European-Non Finnish (NFE) AF: 0.00312 AC: 3435 AN: 1099870

Other (OTH) AF: 0.00133 AC: 79 AN: 59324

GnomAD4 genome AF: 0.00159 AC: 242 AN: 152388 Hom.: 2 Cov.: 33 AF XY: 0.00138 AC XY: 103 AN XY: 74520

African (AFR) AF: 0.000553 AC: 23 AN: 41600

American (AMR) AF: 0.000588 AC: 9 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00295 AC: 201 AN: 68042

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00150 Hom.: 0

Bravo AF: 0.00144

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.000686 AC: 3

ESP6500EA AF: 0.00317 AC: 27

ExAC AF: 0.00144 AC: 173

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	1	2	Propionic acidemia (3)
-	-	2	not specified (2)
-	-	1	PCCB-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Uncertain	0.090
CADD	Benign	14
DANN	Benign	0.92
DEOGEN2	Benign	0.33	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.76	T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.0064	T
MetaSVM	Uncertain	0.40	D
MutationAssessor	Benign	0.0	N
PhyloP100		0.37
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.39	N
REVEL	Uncertain	0.59
Sift	Benign	0.062	T
Sift4G	Benign	0.24	T
Polyphen		0.036	B
Vest4		0.27
MVP		0.67
MPC		0.097
ClinPred		0.019	T
GERP RS		0.74
PromoterAI		0.11	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.077
gMVP		0.44
Mutation Taster		=97/3	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: rs200185747; hg19: chr3-135969266; COSMIC: COSV52443558; COSMIC: COSV52443558;