NM_005125.2:c.636T>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_005125.2(CCS):​c.636T>A​(p.His212Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,613,870 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 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

CCS
NM_005125.2 missense

Scores

6
7
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.788
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.764

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CCSNM_005125.2 linkc.636T>A p.His212Gln missense_variant Exon 7 of 8 ENST00000533244.6 NP_005116.1 O14618

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CCSENST00000533244.6 linkc.636T>A p.His212Gln missense_variant Exon 7 of 8 1 NM_005125.2 ENSP00000436318.1 O14618

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152112
Hom.:
0
Cov.:
32
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:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251258
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135784
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000880
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000130
AC:
19
AN:
1461758
Hom.:
0
Cov.:
32
AF XY:
0.0000138
AC XY:
10
AN XY:
727162
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000153
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152112
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74294
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000468
Hom.:
0
EpiCase
AF:
0.000109
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Sep 08, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.636T>A (p.H212Q) alteration is located in exon 7 (coding exon 7) of the CCS gene. This alteration results from a T to A substitution at nucleotide position 636, causing the histidine (H) at amino acid position 212 to be replaced by a glutamine (Q). 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
Uncertain
0.43
BayesDel_addAF
Pathogenic
0.35
D
BayesDel_noAF
Pathogenic
0.26
CADD
Benign
21
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.77
D;.;D
Eigen
Benign
0.067
Eigen_PC
Benign
0.046
FATHMM_MKL
Uncertain
0.86
D
LIST_S2
Uncertain
0.94
D;D;D
M_CAP
Pathogenic
0.51
D
MetaRNN
Pathogenic
0.76
D;D;D
MetaSVM
Pathogenic
0.91
D
MutationAssessor
Uncertain
2.1
M;.;.
PrimateAI
Benign
0.46
T
PROVEAN
Benign
-1.1
N;N;N
REVEL
Pathogenic
0.77
Sift
Benign
0.084
T;T;D
Sift4G
Uncertain
0.052
T;T;T
Polyphen
0.85
P;.;.
Vest4
0.63
MutPred
0.56
Gain of solvent accessibility (P = 0.0338);.;.;
MVP
0.98
MPC
0.71
ClinPred
0.50
D
GERP RS
0.92
RBP_binding_hub_radar
0.92
RBP_regulation_power_radar
2.6
Varity_R
0.30
gMVP
0.61

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1192088102; hg19: chr11-66373028; API