11-66605384-G-T

Variant names:

• chr11-66605384-G-T
• rs367642079
• NM_005125.2:c.535G>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>T​(p.Ala179Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. A179T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CCS NM_005125.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.87
• Publications: 0 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, 0.877

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>T	p.Ala179Ser	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>T	p.Ala179Ser	missense	Exon 6 of 8	ENSP00000436318.1	O14618
	CCS	ENST00000310190.8	TSL:5	c.478G>T	p.Ala160Ser	missense	Exon 6 of 8	ENSP00000307870.4	J3KNF4
	CCS	ENST00000867839.1		c.535G>T	p.Ala179Ser	missense	Exon 6 of 7	ENSP00000537898.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461882 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727242

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

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

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 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: 0.00 AC: 0 AN: 1112008

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		4.9
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.4	N
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.031	D
Polyphen		0.26	B
Vest4		0.39
MutPred		0.80		Gain of phosphorylation at A179 (P = 0.032)
MVP		0.94
MPC		0.75
ClinPred		0.96	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.74
gMVP		0.73
Mutation Taster		=28/72	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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;