Genetic Variant NM_006833.5:c.53G>A (chr7-100089043-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006833.5(COPS6):c.53G>A(p.Ser18Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000146 in 1,369,294 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 8.2e-7 ( 0 hom. )

Consequence

COPS6
NM_006833.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.54

Publications

0 publications found

Variant links:

Genes affected

COPS6 (HGNC:21749): (COP9 signalosome subunit 6) The protein encoded by this gene is one of the eight subunits of COP9 signalosome, a highly conserved protein complex that functions as an important regulator in multiple signaling pathways. The structure and function of COP9 signalosome is similar to that of the 19S regulatory particle of 26S proteasome. COP9 signalosome has been shown to interact with SCF-type E3 ubiquitin ligases and act as a positive regulator of E3 ubiquitin ligases. This protein belongs to translation initiation factor 3 (eIF3) superfamily. It is involved in the regulation of cell cycle and likely to be a cellular cofactor for HIV-1 accessory gene product Vpr. [provided by RefSeq, Jul 2008]

COPS6 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12526146).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006833.5. 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
	COPS6	NM_006833.5	MANE Select	c.53G>A	p.Ser18Asn	missense	Exon 1 of 10	NP_006824.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COPS6	ENST00000303904.8	TSL:1 MANE Select	c.53G>A	p.Ser18Asn	missense	Exon 1 of 10	ENSP00000304102.3	Q7L5N1
COPS6	ENST00000465027.1	TSL:1	n.75G>A		non_coding_transcript_exon	Exon 1 of 2
COPS6	ENST00000908041.1		c.53G>A	p.Ser18Asn	missense	Exon 1 of 10	ENSP00000578100.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152256

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

8.22e-7

AC:

AN:

1217038

Hom.:

Cov.:

AF XY:

0.00000171

AC XY:

AN XY:

585414

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

24410

American (AMR)

AF:

0.00

AC:

AN:

11880

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16932

East Asian (EAS)

AF:

0.00

AC:

AN:

28150

South Asian (SAS)

AF:

0.00

AC:

AN:

46346

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42816

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4984

European-Non Finnish (NFE)

AF:

0.00000101

AC:

AN:

991640

Other (OTH)

AF:

0.00

AC:

AN:

49880

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152256

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41476

American (AMR)

AF:

0.00

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68046

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.61

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.029

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.66

M_CAP

Benign

0.0084

MetaRNN

Benign

0.13

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

PhyloP100

3.5

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-0.77

REVEL

Benign

0.050

Sift

Benign

0.17

Sift4G

Benign

0.18

Polyphen

0.0

Vest4

0.12

MutPred

0.20

Loss of glycosylation at S18 (P = 0.0014)

MVP

0.39

MPC

0.85

ClinPred

0.77

GERP RS

4.0

PromoterAI

0.031

Neutral

(source)

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

3.7

Varity_R

0.21

gMVP

0.20

Mutation Taster

=78/22

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over