3-149178609-C-G

Position:

chr3-149178609-C-G

Variant summary

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

The ENST00000264613.11(CP):c.2684G>C(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: 𝑓 0.0016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0019 ( 3 hom. )

Consequence

CP
ENST00000264613.11 missense

Scores

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]

CP links:

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/exons	MANE	Protein	UniProt
CP	NM_000096.4 linkuse as main transcript	c.2684G>C	p.Gly895Ala	missense_variant	16/19	ENST00000264613.11	NP_000087.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CP	ENST00000264613.11 linkuse as main transcript	c.2684G>C	p.Gly895Ala	missense_variant	16/19	1	NM_000096.4	ENSP00000264613	P1

Frequencies

GnomAD3 genomes

AF:

0.00156

AC:

237

AN:

151782

Hom.:

Cov.:

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.:

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.:

Cov.:

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.:

Cov.:

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.:

Bravo

AF:

0.00191

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00186

AC:

ExAC

AF:

0.00147

AC:

178

Asia WGS

AF:

0.000289

AC:

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

Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, no assertion criteria provided	curation	GeneReviews	Apr 18, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Jan 27, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -

not provided

Uncertain:5Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 13, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 09, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 30, 2024	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) -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	CP: PP3, BP2, BS1 -

not specified

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 04, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 13, 2023	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

Likely pathogenic, flagged submission

clinical testing

DASA

Feb 14, 2022

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

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 17, 2024

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

BayesDel_noAF

Pathogenic

0.55

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.49

T;.;D

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.99

D;.;D

M_CAP

Uncertain

0.24

MetaRNN

Benign

0.15

T;T;T

MetaSVM

Uncertain

0.77

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.71

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over