rs115552500

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000096.4(CP):c.2378G>A(p.Arg793His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00991 in 1,611,260 control chromosomes in the GnomAD database, including 104 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R793C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.012 ( 16 hom., cov: 31)

Exomes 𝑓: 0.0097 ( 88 hom. )

Consequence

CP
NM_000096.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -1.42

Publications

19 publications found

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 Gene-Disease associations (from GenCC):

aceruloplasminemia
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
disorder of iron metabolism and transport
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

CP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006608665).

BP6

Variant 3-149183513-C-T is Benign according to our data. Variant chr3-149183513-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0118 (1796/151754) while in subpopulation AFR AF = 0.0194 (802/41354). AF 95% confidence interval is 0.0183. There are 16 homozygotes in GnomAd4. There are 866 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 16 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CP	NM_000096.4 link	c.2378G>A	p.Arg793His	missense_variant	Exon 13 of 19	ENST00000264613.11	NP_000087.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CP	ENST00000264613.11 link	c.2378G>A	p.Arg793His	missense_variant	Exon 13 of 19	1	NM_000096.4	ENSP00000264613.6
CP	ENST00000494544.1 link	c.1727G>A	p.Arg576His	missense_variant	Exon 10 of 16	1		ENSP00000420545.1
CP	ENST00000490639.5 link	n.2410G>A		non_coding_transcript_exon_variant	Exon 13 of 17	1
CP	ENST00000481169.5 link	n.2165G>A		non_coding_transcript_exon_variant	Exon 12 of 18	2		ENSP00000418773.1

Frequencies

GnomAD3 genomes

AF:

0.0118

AC:

1794

AN:

151636

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0194

Gnomad AMI

AF:

0.0384

Gnomad AMR

AF:

0.0121

Gnomad ASJ

AF:

0.00663

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.000768

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0102

Gnomad OTH

AF:

0.0163

GnomAD2 exomes

AF:

0.00731

AC:

1838

AN:

251338

AF XY:

0.00710

show subpopulations

Gnomad AFR exome

AF:

0.0202

Gnomad AMR exome

AF:

0.00746

Gnomad ASJ exome

AF:

0.00595

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.000741

Gnomad NFE exome

AF:

0.00883

Gnomad OTH exome

AF:

0.0116

GnomAD4 exome

AF:

0.00971

AC:

14175

AN:

1459506

Hom.:

Cov.:

AF XY:

0.00953

AC XY:

6922

AN XY:

726084

show subpopulations

African (AFR)

AF:

0.0178

AC:

595

AN:

33412

American (AMR)

AF:

0.00756

AC:

338

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00574

AC:

150

AN:

26126

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39644

South Asian (SAS)

AF:

0.00312

AC:

269

AN:

86154

European-Finnish (FIN)

AF:

0.00152

AC:

AN:

53240

Middle Eastern (MID)

AF:

0.0134

AC:

AN:

4462

European-Non Finnish (NFE)

AF:

0.0109

AC:

12060

AN:

1111522

Other (OTH)

AF:

0.0103

AC:

621

AN:

60224

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

655

1310

1964

2619

3274

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

474

948

1422

1896

2370

<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

AF:

0.0118

AC:

1796

AN:

151754

Hom.:

Cov.:

AF XY:

0.0117

AC XY:

866

AN XY:

74108

show subpopulations

African (AFR)

AF:

0.0194

AC:

802

AN:

41354

American (AMR)

AF:

0.0121

AC:

184

AN:

15246

Ashkenazi Jewish (ASJ)

AF:

0.00663

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5168

South Asian (SAS)

AF:

0.00291

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.000768

AC:

AN:

10416

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0102

AC:

690

AN:

67968

Other (OTH)

AF:

0.0161

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

184

277

369

461

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00980

Hom.:

Bravo

AF:

0.0124

TwinsUK

AF:

0.0140

AC:

ALSPAC

AF:

0.00908

AC:

ESP6500AA

AF:

0.0202

AC:

ESP6500EA

AF:

0.00919

AC:

ExAC

AF:

0.00708

AC:

860

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.0108

EpiControl

AF:

0.0106

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Dec 10, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 04, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Deficiency of ferroxidase

Benign:3

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Jan 04, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Mar 30, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 15557511, 25758665, 26000822, 16150804)

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

CP-related disorder

Benign:1

Mar 25, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.0

.;T

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.040

LIST_S2

Benign

0.0

.;D

MetaRNN

Benign

0.0066

T;T

MetaSVM

Uncertain

0.46

MutationAssessor

Benign

0.0

.;.

PhyloP100

-1.4

PrimateAI

Benign

0.22

PROVEAN

Benign

-1.9

N;N

REVEL

Uncertain

0.34

Sift

Benign

0.12

T;T

Sift4G

Benign

0.12

T;T

Vest4

0.15

ClinPred

0.012

GERP RS

-1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.50

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over