3-136250380-CGGCGGCATTACGGGT-C

Variant names:

• chr3-136250380-CGGCGGCATTACGGGT-C
• rs1553773148
• NM_000532.5:c.12_26delATTACGGGTGGCGGC

Variant summary

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

The NM_000532.5(PCCB):​c.12_26delATTACGGGTGGCGGC​(p.Leu5_Ala9del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000189 in 1,374,506 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 DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A4A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: PCCB NM_000532.5 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 2.54
• 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 2 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_000532.5.

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.12_26delATTACGGGTGGCGGC	p.Leu5_Ala9del	disruptive_inframe_deletion	Exon 1 of 15	NP_000523.2	P05166-1
	PCCB	NM_001178014.2		c.12_26delATTACGGGTGGCGGC	p.Leu5_Ala9del	disruptive_inframe_deletion	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.12_26delATTACGGGTGGCGGC	p.Leu5_Ala9del	disruptive_inframe_deletion	Exon 1 of 15	ENSP00000251654.4	P05166-1
	PCCB	ENST00000471595.5	TSL:1	c.12_26delATTACGGGTGGCGGC	p.Leu5_Ala9del	disruptive_inframe_deletion	Exon 1 of 16	ENSP00000417549.1	E9PDR0
	PCCB	ENST00000478469.5	TSL:1	c.12_26delATTACGGGTGGCGGC	p.Leu5_Ala9del	disruptive_inframe_deletion	Exon 1 of 9	ENSP00000420759.1	E7ENC1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000189 AC: 26 AN: 1374506 Hom.: 0 AF XY: 0.0000163 AC XY: 11 AN XY: 674546

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31118

American (AMR) AF: 0.00 AC: 0 AN: 34426

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22436

East Asian (EAS) AF: 0.00 AC: 0 AN: 36514

South Asian (SAS) AF: 0.00 AC: 0 AN: 75128

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48154

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5188

European-Non Finnish (NFE) AF: 0.0000244 AC: 26 AN: 1064934

Other (OTH) AF: 0.00 AC: 0 AN: 56608

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000000675803), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	2	-	Propionic acidemia (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.5

Splicing

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

Other links and lift over

dbSNP: rs1553773148; hg19: chr3-135969222;