Genetic Variant CCS:p.Arg209Pro (chr11-66605547-G-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_005125.2(CCS):c.626G>C(p.Arg209Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,352 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R209Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CCS
NM_005125.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.26

Publications

0 publications found

Variant links:

Genes affected

CCS (HGNC:1613): (copper chaperone for superoxide dismutase) Copper chaperone for superoxide dismutase specifically delivers Cu to copper/zinc superoxide dismutase and may activate copper/zinc superoxide dismutase through direct insertion of the Cu cofactor. [provided by RefSeq, Jul 2008]

CCS Gene-Disease associations (from GenCC):

disorder of copper metabolism
Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

CCS links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3346696).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005125.2. 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
	CCS	NM_005125.2	MANE Select	c.626G>C	p.Arg209Pro	missense	Exon 7 of 8	NP_005116.1	O14618

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CCS	ENST00000533244.6	TSL:1 MANE Select	c.626G>C	p.Arg209Pro	missense	Exon 7 of 8	ENSP00000436318.1	O14618
CCS	ENST00000310190.8	TSL:5	c.569G>C	p.Arg190Pro	missense	Exon 7 of 8	ENSP00000307870.4	J3KNF4
CCS	ENST00000939538.1		c.548G>C	p.Arg183Pro	missense	Exon 6 of 7	ENSP00000609597.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461352

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726978

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86206

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111598

Other (OTH)

AF:

0.00

AC:

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Uncertain

0.025

BayesDel_noAF

Benign

-0.20

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.91

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.63

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.016

MetaRNN

Benign

0.33

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

PhyloP100

1.3

PrimateAI

Benign

0.30

PROVEAN

Uncertain

-3.3

REVEL

Benign

0.28

Sift

Benign

0.16

Sift4G

Benign

0.075

Polyphen

0.0080

Vest4

0.80

MutPred

0.54

Loss of solvent accessibility (P = 0.0703)

MVP

0.39

MPC

0.87

ClinPred

0.83

GERP RS

-1.8

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.0

Varity_R

0.77

gMVP

0.76

Mutation Taster

=44/56

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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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