rs367642079

Variant names:

• chr11-66605384-G-A
• rs367642079
• NM_005125.2:c.535G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-66605384-G-A
• chr11-66605384-G-T

Variant summary

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

The NM_005125.2(CCS):​c.535G>A​(p.Ala179Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000713 in 1,614,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000073 (0 hom.)
• Consequence: CCS NM_005125.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.87
• Publications: 3 publications found

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

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, 0.861

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.535G>A	p.Ala179Thr	missense	Exon 6 of 8	NP_005116.1	O14618

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCS	ENST00000533244.6	TSL:1 MANE Select	c.535G>A	p.Ala179Thr	missense	Exon 6 of 8	ENSP00000436318.1	O14618
	CCS	ENST00000310190.8	TSL:5	c.478G>A	p.Ala160Thr	missense	Exon 6 of 8	ENSP00000307870.4	J3KNF4
	CCS	ENST00000867839.1		c.535G>A	p.Ala179Thr	missense	Exon 6 of 7	ENSP00000537898.1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152140 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000438 AC: 11 AN: 251394 AF XY: 0.0000147

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000272

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000732 AC: 107 AN: 1461882 Hom.: 0 Cov.: 32 AF XY: 0.0000674 AC XY: 49 AN XY: 727242

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000782 AC: 87 AN: 1112008

Other (OTH) AF: 0.000199 AC: 12 AN: 60396

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152140 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74324

African (AFR) AF: 0.00 AC: 0 AN: 41418

American (AMR) AF: 0.0000655 AC: 1 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000965 Hom.: 0

Bravo AF: 0.0000756

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

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	Benign	0.20
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		4.9
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.2	D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.021	D
Polyphen		0.99	D
Vest4		0.65
MVP		0.96
MPC		0.81
ClinPred		0.73	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.79
gMVP		0.79
Mutation Taster		=55/45	polymorphism

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: rs367642079; hg19: chr11-66372855; COSMIC: COSV100039972; COSMIC: COSV100039972;