2-231070166-C-G

Variant names:

• chr2-231070166-C-G
• NM_002807.4:c.652C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002807.4(PSMD1):​c.652C>G​(p.Gln218Glu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PSMD1 NM_002807.4 missense, splice_region
• Scores: Splicing: ADA: 0.9613
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

Genes affected

PSMD1 (HGNC:9554): (proteasome 26S subunit, non-ATPase 1) 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 the largest non-ATPase subunit of the 19S regulator lid, which is responsible for substrate recognition and binding. There is evidence that this proteasome and its subunits interact with viral proteins, including those of coronaviruses. Alternatively spliced transcript variants have been found for this gene.[provided by RefSeq, Aug 2020]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSMD1	NM_002807.4	c.652C>G	p.Gln218Glu	missense_variant, splice_region_variant	Exon 6 of 25	ENST00000308696.11	NP_002798.2
PSMD1	NM_001191037.2	c.652C>G	p.Gln218Glu	missense_variant, splice_region_variant	Exon 6 of 24		NP_001177966.1
PSMD1	XM_017004517.3	c.652C>G	p.Gln218Glu	missense_variant, splice_region_variant	Exon 6 of 18		XP_016860006.1
PSMD1	NR_034059.2	n.641C>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 5 of 24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSMD1	ENST00000308696.11	c.652C>G	p.Gln218Glu	missense_variant, splice_region_variant	Exon 6 of 25	1	NM_002807.4	ENSP00000309474.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.652C>G (p.Q218E) alteration is located in exon 6 (coding exon 6) of the PSMD1 gene. This alteration results from a C to G substitution at nucleotide position 652, causing the glutamine (Q) at amino acid position 218 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	.;T;.;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;.;D
M_CAP	Benign	0.025	T
MetaRNN	Uncertain	0.70	D;D;D;D
MetaSVM	Benign	-0.31	T
MutationAssessor	Uncertain	2.3	M;M;M;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-2.8	D;D;D;.
REVEL	Uncertain	0.56
Sift	Uncertain	0.0020	D;D;D;.
Sift4G	Uncertain	0.0050	D;D;D;D
Polyphen		0.86	P;P;P;.
Vest4		0.71
MutPred		0.53		Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);
MVP		0.74
MPC		1.0
ClinPred		0.82	D
GERP RS		5.8
Varity_R		0.74
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.96
dbscSNV1_RF	Benign	0.67
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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-231934880;