chr1-175989434-A-C

Variant names:

• chr1-175989434-A-C
• rs749820946
• NM_022457.7:c.1775T>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_022457.7(COP1):​c.1775T>G​(p.Ile592Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000686 in 1,457,706 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I592V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: COP1 NM_022457.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.10
• Publications: 2 publications found

Genes affected

COP1 (HGNC:17440): (COP1 E3 ubiquitin ligase) Enables ubiquitin protein ligase activity. Involved in positive regulation of proteasomal ubiquitin-dependent protein catabolic process; proteasome-mediated ubiquitin-dependent protein catabolic process; and response to ionizing radiation. Part of Cul4A-RING E3 ubiquitin ligase complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 10 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022457.7. 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
	COP1	NM_022457.7	MANE Select	c.1775T>G	p.Ile592Ser	missense	Exon 16 of 20	NP_071902.2
	COP1	NM_001001740.4		c.1703T>G	p.Ile568Ser	missense	Exon 15 of 19	NP_001001740.1	Q8NHY2-2
	COP1	NM_001286644.2		c.1055T>G	p.Ile352Ser	missense	Exon 14 of 18	NP_001273573.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COP1	ENST00000367669.8	TSL:1 MANE Select	c.1775T>G	p.Ile592Ser	missense	Exon 16 of 20	ENSP00000356641.3	Q8NHY2-1
	COP1	ENST00000308769.12	TSL:1	c.1703T>G	p.Ile568Ser	missense	Exon 15 of 19	ENSP00000310943.8	Q8NHY2-2
	COP1	ENST00000367667.5	TSL:1	n.*951T>G		non_coding_transcript_exon	Exon 14 of 18	ENSP00000356639.1	H0Y340

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000798 AC: 2 AN: 250698 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000686 AC: 10 AN: 1457706 Hom.: 0 Cov.: 28 AF XY: 0.00000965 AC XY: 7 AN XY: 725470

African (AFR) AF: 0.00 AC: 0 AN: 33394

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39600

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86186

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108304

Other (OTH) AF: 0.00 AC: 0 AN: 60248

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Benign	-0.63	T
PhyloP100		9.1
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.50
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.98	D
Vest4		0.87
MutPred		0.37		Gain of disorder (P = 0.0102)
MVP		0.52
MPC		1.9
ClinPred		0.80	D
GERP RS		5.8
Varity_R		0.80
gMVP		0.69
Mutation Taster		=24/76	disease causing

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: rs749820946; hg19: chr1-175958570;