chr3-149178609-C-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP3BP4_ModerateBS2

The NM_000096.4(CP):ā€‹c.2684G>Cā€‹(p.Gly895Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00182 in 1,611,726 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: š‘“ 0.0016 ( 0 hom., cov: 32)
Exomes š‘“: 0.0019 ( 3 hom. )

Consequence

CP
NM_000096.4 missense

Scores

10
6
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:11B:3

Conservation

PhyloP100: 7.57
Variant links:
Genes affected
CP (HGNC:2295): (ceruloplasmin) The protein encoded by this gene is a metalloprotein that binds most of the copper in plasma and is involved in the peroxidation of Fe(II)transferrin to Fe(III) transferrin. Mutations in this gene cause aceruloplasminemia, which results in iron accumulation and tissue damage, and is associated with diabetes and neurologic abnormalities. Two transcript variants, one protein-coding and the other not protein-coding, have been found for this gene. [provided by RefSeq, Feb 2012]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PP3
Multiple lines of computational evidence support a deleterious effect 6: BayesDel_addAF, BayesDel_noAF, Eigen, phyloP100way_vertebrate, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
BP4
Computational evidence support a benign effect (MetaRNN=0.14648741).
BS2
High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CPNM_000096.4 linkc.2684G>C p.Gly895Ala missense_variant Exon 16 of 19 ENST00000264613.11 NP_000087.2 P00450A5PL27

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CPENST00000264613.11 linkc.2684G>C p.Gly895Ala missense_variant Exon 16 of 19 1 NM_000096.4 ENSP00000264613.6 P00450

Frequencies

GnomAD3 genomes
AF:
0.00156
AC:
237
AN:
151782
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000291
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00308
Gnomad ASJ
AF:
0.00115
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00161
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00219
Gnomad OTH
AF:
0.00383
GnomAD3 exomes
AF:
0.00152
AC:
380
AN:
250058
Hom.:
0
AF XY:
0.00160
AC XY:
217
AN XY:
135310
show subpopulations
Gnomad AFR exome
AF:
0.000501
Gnomad AMR exome
AF:
0.00244
Gnomad ASJ exome
AF:
0.00169
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000983
Gnomad FIN exome
AF:
0.00144
Gnomad NFE exome
AF:
0.00203
Gnomad OTH exome
AF:
0.00115
GnomAD4 exome
AF:
0.00185
AC:
2703
AN:
1459826
Hom.:
3
Cov.:
31
AF XY:
0.00186
AC XY:
1354
AN XY:
726376
show subpopulations
Gnomad4 AFR exome
AF:
0.000299
Gnomad4 AMR exome
AF:
0.00271
Gnomad4 ASJ exome
AF:
0.00126
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000812
Gnomad4 FIN exome
AF:
0.00111
Gnomad4 NFE exome
AF:
0.00213
Gnomad4 OTH exome
AF:
0.00172
GnomAD4 genome
AF:
0.00156
AC:
237
AN:
151900
Hom.:
0
Cov.:
32
AF XY:
0.00148
AC XY:
110
AN XY:
74260
show subpopulations
Gnomad4 AFR
AF:
0.000290
Gnomad4 AMR
AF:
0.00308
Gnomad4 ASJ
AF:
0.00115
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00161
Gnomad4 NFE
AF:
0.00219
Gnomad4 OTH
AF:
0.00379
Alfa
AF:
0.00190
Hom.:
0
Bravo
AF:
0.00191
TwinsUK
AF:
0.00378
AC:
14
ALSPAC
AF:
0.00234
AC:
9
ESP6500AA
AF:
0.000454
AC:
2
ESP6500EA
AF:
0.00186
AC:
16
ExAC
AF:
0.00147
AC:
178
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.00180
EpiControl
AF:
0.00232

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:11Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Deficiency of ferroxidase Pathogenic:1Uncertain:4Benign:1
Apr 18, 2013
GeneReviews
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: curation

- -

-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Jan 27, 2022
Mendelics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 31, 2018
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 27, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Uncertain:5Benign:1
Aug 09, 2016
Eurofins Ntd Llc (ga)
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Sep 13, 2016
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 30, 2024
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(G876A); This variant is associated with the following publications: (PMID: 27753142, 28968711, 18293024, 16629161, 34426522, 31785789, 33774058, 34274368, 36233161, 37784196, 32235485, 36757662) -

Aug 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

CP: PP3, BP2, BS1 -

not specified Uncertain:1Benign:1
Mar 04, 2016
Genetic Services Laboratory, University of Chicago
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 13, 2023
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: CP c.2684G>C (p.Gly895Ala) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0015 in 250058 control chromosomes (gnomAD), predominantly at a frequency of 0.0024 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 13 fold of the estimated maximal expected allele frequency for a pathogenic variant in CP causing Neurodegeneration With Brain Iron Accumulation (0.00019), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. Ten ClinVar submitters have assessed the variant since 2014: seven classified the variant as uncertain significance, one as likely pathogenic, and two as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

Hypoceruloplasminemia Pathogenic:1
Feb 14, 2022
DASA
Significance: Likely pathogenic
Review Status: flagged submission
Collection Method: clinical testing

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (DOI:10.1016/j.mgene.2021.100905) - PS3_supporting. The c.2684G>C;p.(Gly895Ala) missense variant has been observed in affected individual(s) (PMID: 32235485; 27753142; 20301666; https://doi.org/10.1016/j.mgene.2021.100905) - PS4_supporting. The variant is present at low allele frequencies population databases (rs139633388 - gnomAD 0.01561%; ABraOM 0.000854 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Gly895Ala) was detected in trans with a pathogenic variant (PMID: 32235485; 27753142; https://doi.org/10.1016/j.mgene.2021.100905) - PM3_strong. The variant co-segregated with disease in multiple affected family members (PMID: 32235485) - PP1. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is likely pathogenic. -

CP-related disorder Uncertain:1
Jul 17, 2024
PreventionGenetics, part of Exact Sciences
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

The CP c.2684G>C variant is predicted to result in the amino acid substitution p.Gly895Ala. This variant has been reported in patients with aceruloplasminemia, although conclusive evidence of pathogenicity was not presented (reported as G876A in Kono et al. 2006. PubMed ID: 16629161; Vila Cuenca et al. 2020. PubMed ID: 32235485). This variant is reported in 0.25% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.56
BayesDel_addAF
Pathogenic
0.23
D
BayesDel_noAF
Pathogenic
0.55
CADD
Uncertain
26
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.49
T;.;D
Eigen
Pathogenic
0.94
Eigen_PC
Pathogenic
0.88
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Pathogenic
0.99
D;.;D
M_CAP
Uncertain
0.24
D
MetaRNN
Benign
0.15
T;T;T
MetaSVM
Uncertain
0.77
D
PrimateAI
Uncertain
0.71
T
PROVEAN
Pathogenic
-5.8
D;D;D
REVEL
Pathogenic
0.95
Sift
Pathogenic
0.0
D;D;D
Sift4G
Pathogenic
0.0
D;D;D
Vest4
0.98
MVP
0.96
MPC
0.50
ClinPred
0.057
T
GERP RS
5.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
gMVP
0.96

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs139633388; hg19: chr3-148896396; API