Genetic Variant NM_005125.2:c.449C>A (chr11-66600509-C-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_005125.2(CCS):c.449C>A(p.Pro150His) variant causes a missense change. The variant allele was found at a frequency of 0.000000719 in 1,390,678 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. P150L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

CCS
NM_005125.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.23

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 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.919

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.449C>A	p.Pro150His	missense	Exon 5 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.449C>A	p.Pro150His	missense	Exon 5 of 8	ENSP00000436318.1	O14618
CCS	ENST00000534763.1	TSL:2	c.-98C>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 4	ENSP00000436379.1	E9PP76
CCS	ENST00000310190.8	TSL:5	c.392C>A	p.Pro131His	missense	Exon 5 of 8	ENSP00000307870.4	J3KNF4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.19e-7

AC:

AN:

1390678

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

691404

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

30528

American (AMR)

AF:

0.00

AC:

AN:

36766

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24504

East Asian (EAS)

AF:

0.00

AC:

AN:

35314

South Asian (SAS)

AF:

0.00

AC:

AN:

76298

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51984

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5486

European-Non Finnish (NFE)

AF:

9.32e-7

AC:

AN:

1072856

Other (OTH)

AF:

0.00

AC:

AN:

56942

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

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

Uncertain

0.40

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.98

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.62

MetaRNN

Pathogenic

0.92

MetaSVM

Pathogenic

0.97

MutationAssessor

Pathogenic

3.5

PhyloP100

6.2

PrimateAI

Uncertain

0.53

PROVEAN

Pathogenic

-7.4

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.86

MutPred

0.59

Gain of catalytic residue at P150 (P = 0.0695)

MVP

0.99

MPC

0.97

ClinPred

1.0

GERP RS

5.2

PromoterAI

0.011

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.94

gMVP

0.86

Mutation Taster

=3/97

disease causing

(source)

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

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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