17-63831196-C-G

Variant names:

• chr17-63831196-C-G
• rs13030
• NM_002805.6:c.840C>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_002805.6(PSMC5):​c.840C>G​(p.Leu280Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L280L) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PSMC5 NM_002805.6 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0630
• Publications: 35 publications found

Genes affected

PSMC5 (HGNC:9552): (proteasome 26S subunit, ATPase 5) The 26S proteasome is a multicatalytic proteinase complex with a highly ordered structure composed of 2 complexes, a 20S core and a 19S regulator. The 20S core is composed of 4 rings of 28 non-identical subunits; 2 rings are composed of 7 alpha subunits and 2 rings are composed of 7 beta subunits. The 19S regulator is composed of a base, which contains 6 ATPase subunits and 2 non-ATPase subunits, and a lid, which contains up to 10 non-ATPase subunits. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway. An essential function of a modified proteasome, the immunoproteasome, is the processing of class I MHC peptides. This gene encodes one of the ATPase subunits, a member of the triple-A family of ATPases which have a chaperone-like activity. In addition to participation in proteasome functions, this subunit may participate in transcriptional regulation since it has been shown to interact with the thyroid hormone receptor and retinoid X receptor-alpha. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2010]

PSMC5 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder

  Inheritance: AD Classification: MODERATE Submitted by: G2P, Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP7: Synonymous conserved (PhyloP=-0.063 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002805.6. 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
	PSMC5	NM_002805.6	MANE Select	c.840C>G	p.Leu280Leu	synonymous	Exon 8 of 12	NP_002796.4
	PSMC5	NM_001199163.2		c.816C>G	p.Leu272Leu	synonymous	Exon 8 of 12	NP_001186092.1	P62195-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSMC5	ENST00000310144.11	TSL:1 MANE Select	c.840C>G	p.Leu280Leu	synonymous	Exon 8 of 12	ENSP00000310572.6	P62195-1
	PSMC5	ENST00000961598.1		c.834C>G	p.Leu278Leu	synonymous	Exon 8 of 12	ENSP00000631657.1
	PSMC5	ENST00000935074.1		c.840C>G	p.Leu280Leu	synonymous	Exon 8 of 12	ENSP00000605133.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1407430 Hom.: 0 Cov.: 47 AF XY: 0.00 AC XY: 0 AN XY: 693972

African (AFR) AF: 0.00 AC: 0 AN: 31690

American (AMR) AF: 0.00 AC: 0 AN: 37574

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22466

East Asian (EAS) AF: 0.00 AC: 0 AN: 39140

South Asian (SAS) AF: 0.00 AC: 0 AN: 78334

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51672

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5476

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1083256

Other (OTH) AF: 0.00 AC: 0 AN: 57822

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 35933

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	2.8
DANN	Benign	0.78
PhyloP100		-0.063

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: rs13030; hg19: chr17-61908556;