rs968719

Variant names:

• chr17-63830911-C-G
• rs968719
• NM_002805.6:c.655C>G

Your query was ambiguous. Multiple possible variants found:

• chr17-63830911-C-G
• chr17-63830911-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002805.6(PSMC5):​c.655C>G​(p.Leu219Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as (no stars). Synonymous variant affecting the same amino acid position (i.e. L219L) has been classified as Benign.

• Frequency: Genomes: not found (cov: 29)
• Consequence: PSMC5 NM_002805.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00700
• Publications: 38 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.929

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.655C>G	p.Leu219Val	missense	Exon 7 of 12	NP_002796.4
	PSMC5	NM_001199163.2		c.631C>G	p.Leu211Val	missense	Exon 7 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.655C>G	p.Leu219Val	missense	Exon 7 of 12	ENSP00000310572.6	P62195-1
	PSMC5	ENST00000961598.1		c.649C>G	p.Leu217Val	missense	Exon 7 of 12	ENSP00000631657.1
	PSMC5	ENST00000935074.1		c.655C>G	p.Leu219Val	missense	Exon 7 of 12	ENSP00000605133.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 65

GnomAD4 genome Cov.: 29

Alfa AF: 0.00 Hom.: 37480

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.64	D
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.64	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.00050	D
MutationAssessor	Benign	1.1	L
PhyloP100		-0.0070
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.014	D
Polyphen		0.98	D
Vest4		0.83
MutPred		0.76		Gain of MoRF binding (P = 0.1031)
MVP		0.91
MPC		2.3
ClinPred		0.99	D
GERP RS		-3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
gMVP		0.95

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: rs968719; hg19: chr17-61908271;