11-66605563-A-C

Variant names:

• chr11-66605563-A-C
• NM_005125.2:c.642A>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005125.2(CCS):​c.642A>C​(p.Leu214Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CCS NM_005125.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.412

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCS	NM_005125.2	c.642A>C	p.Leu214Phe	missense_variant	Exon 7 of 8	ENST00000533244.6	NP_005116.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCS	ENST00000533244.6	c.642A>C	p.Leu214Phe	missense_variant	Exon 7 of 8	1	NM_005125.2	ENSP00000436318.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.642A>C (p.L214F) alteration is located in exon 7 (coding exon 7) of the CCS gene. This alteration results from a A to C substitution at nucleotide position 642, causing the leucine (L) at amino acid position 214 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D;.;T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.38	N
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Pathogenic	0.75	D
MetaRNN	Uncertain	0.57	D;D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Uncertain	2.8	M;.;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.96	N;N;N
REVEL	Pathogenic	0.67
Sift	Benign	0.073	T;T;D
Sift4G	Benign	0.10	T;T;T
Polyphen		0.97	D;.;.
Vest4		0.55
MutPred		0.44		Loss of ubiquitination at K216 (P = 0.0731);.;.;
MVP		0.97
MPC		0.87
ClinPred		0.97	D
GERP RS		-2.6
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.16
gMVP		0.44

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-66373034;