Genetic Variant NM_000532.5:c.28_29insCATTACGGGTGGCGGCGGCATTACGGGTGGCGGCGG (chr3-136250376-A-ATGGCGGCGGCATTACGGGTGGCGGCGGCATTACGGG) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM4

The NM_000532.5(PCCB):c.28_29insCATTACGGGTGGCGGCGGCATTACGGGTGGCGGCGG(p.Ala9_Val10insAlaLeuArgValAlaAlaAlaLeuArgValAlaAla) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000146 in 1,373,862 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. V10V) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

PCCB
NM_000532.5 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.47

Publications

0 publications found

Variant links:

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: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Myriad Women’s Health, Orphanet

PCCB links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_000532.5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCCB	NM_000532.5 link	c.28_29insCATTACGGGTGGCGGCGGCATTACGGGTGGCGGCGG	p.Ala9_Val10insAlaLeuArgValAlaAlaAlaLeuArgValAlaAla	disruptive_inframe_insertion	Exon 1 of 15	ENST00000251654.9	NP_000523.2	P05166-1
PCCB	NM_001178014.2 link	c.28_29insCATTACGGGTGGCGGCGGCATTACGGGTGGCGGCGG	p.Ala9_Val10insAlaLeuArgValAlaAlaAlaLeuArgValAlaAla	disruptive_inframe_insertion	Exon 1 of 16		NP_001171485.1	P05166-2
PCCB	XM_011512873.2 link	c.28_29insCATTACGGGTGGCGGCGGCATTACGGGTGGCGGCGG	p.Ala9_Val10insAlaLeuArgValAlaAlaAlaLeuArgValAlaAla	disruptive_inframe_insertion	Exon 1 of 11		XP_011511175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCCB	ENST00000251654.9 link	c.28_29insCATTACGGGTGGCGGCGGCATTACGGGTGGCGGCGG	p.Ala9_Val10insAlaLeuArgValAlaAlaAlaLeuArgValAlaAla	disruptive_inframe_insertion	Exon 1 of 15	1	NM_000532.5	ENSP00000251654.4		P05166-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000146

AC:

AN:

1373862

Hom.:

Cov.:

AF XY:

0.00000297

AC XY:

AN XY:

674084

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31114

American (AMR)

AF:

0.00

AC:

AN:

34398

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22408

East Asian (EAS)

AF:

0.0000548

AC:

AN:

36518

South Asian (SAS)

AF:

0.00

AC:

AN:

74892

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48100

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5198

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1064668

Other (OTH)

AF:

0.00

AC:

AN:

56566

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.5

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over