3-136250391-C-G

Variant names:

• chr3-136250391-C-G
• rs377681768
• NM_000532.5:c.16C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_000532.5(PCCB):​c.16C>G​(p.Arg6Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000723 in 1,383,414 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R6L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: PCCB NM_000532.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.730
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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=0.23658893).

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.16C>G	p.Arg6Gly	missense	Exon 1 of 15	NP_000523.2	P05166-1
	PCCB	NM_001178014.2		c.16C>G	p.Arg6Gly	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.16C>G	p.Arg6Gly	missense	Exon 1 of 15	ENSP00000251654.4	P05166-1
	PCCB	ENST00000471595.5	TSL:1	c.16C>G	p.Arg6Gly	missense	Exon 1 of 16	ENSP00000417549.1	E9PDR0
	PCCB	ENST00000478469.5	TSL:1	c.16C>G	p.Arg6Gly	missense	Exon 1 of 9	ENSP00000420759.1	E7ENC1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000643 AC: 1 AN: 155458 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000156

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.23e-7 AC: 1 AN: 1383414 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 680322

African (AFR) AF: 0.00 AC: 0 AN: 31326

American (AMR) AF: 0.00 AC: 0 AN: 35224

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22980

East Asian (EAS) AF: 0.00 AC: 0 AN: 36622

South Asian (SAS) AF: 0.00 AC: 0 AN: 76910

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48478

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5366

European-Non Finnish (NFE) AF: 9.35e-7 AC: 1 AN: 1069518

Other (OTH) AF: 0.00 AC: 0 AN: 56990

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	19
DANN	Benign	0.87
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.24	T
MetaSVM	Uncertain	0.23	D
MutationAssessor	Benign	0.0	N
PhyloP100		0.73
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.51
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.18	T
Polyphen		0.67	P
Vest4		0.31
MutPred		0.49		Loss of MoRF binding (P = 2e-04)
MVP		0.81
MPC		0.13
ClinPred		0.48	T
GERP RS		2.1
PromoterAI		-0.097	Neutral
Varity_R		0.26
gMVP		0.60
Mutation Taster		=95/5	polymorphism

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: rs377681768; hg19: chr3-135969233;