NM_000096.4:c.1652C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000096.4(CP):c.1652C>T(p.Thr551Ile) variant causes a missense change. The variant allele was found at a frequency of 0.031 in 1,612,482 control chromosomes in the GnomAD database, including 978 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.023 ( 65 hom., cov: 32)

Exomes 𝑓: 0.032 ( 913 hom. )

Consequence

CP
NM_000096.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:13

Conservation

PhyloP100: 6.57

Publications

15 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=0.01101324).

BP6

Variant 3-149198428-G-A is Benign according to our data. Variant chr3-149198428-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 42125.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0549 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CP	NM_000096.4 link	c.1652C>T	p.Thr551Ile	missense_variant	Exon 9 of 19	ENST00000264613.11	NP_000087.2	P00450A5PL27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CP	ENST00000264613.11 link	c.1652C>T	p.Thr551Ile	missense_variant	Exon 9 of 19	1	NM_000096.4	ENSP00000264613.6		P00450

Frequencies

GnomAD3 genomes

AF:

0.0227

AC:

3460

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00655

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0191

Gnomad ASJ

AF:

0.0294

Gnomad EAS

AF:

0.00192

Gnomad SAS

AF:

0.0610

Gnomad FIN

AF:

0.0188

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0326

Gnomad OTH

AF:

0.0268

GnomAD2 exomes

AF:

0.0285

AC:

7148

AN:

251032

AF XY:

0.0311

show subpopulations

Gnomad AFR exome

AF:

0.00591

Gnomad AMR exome

AF:

0.0167

Gnomad ASJ exome

AF:

0.0326

Gnomad EAS exome

AF:

0.000544

Gnomad FIN exome

AF:

0.0227

Gnomad NFE exome

AF:

0.0307

Gnomad OTH exome

AF:

0.0304

GnomAD4 exome

AF:

0.0319

AC:

46572

AN:

1460234

Hom.:

913

Cov.:

AF XY:

0.0330

AC XY:

23995

AN XY:

726518

show subpopulations

African (AFR)

AF:

0.00568

AC:

190

AN:

33472

American (AMR)

AF:

0.0170

AC:

762

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0300

AC:

783

AN:

26128

East Asian (EAS)

AF:

0.00222

AC:

AN:

39694

South Asian (SAS)

AF:

0.0646

AC:

5569

AN:

86180

European-Finnish (FIN)

AF:

0.0235

AC:

1254

AN:

53412

Middle Eastern (MID)

AF:

0.0472

AC:

272

AN:

5764

European-Non Finnish (NFE)

AF:

0.0322

AC:

35770

AN:

1110522

Other (OTH)

AF:

0.0312

AC:

1884

AN:

60346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

2079

4158

6236

8315

10394

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1354

2708

4062

5416

6770

<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:

0.0227

AC:

3456

AN:

152248

Hom.:

Cov.:

AF XY:

0.0227

AC XY:

1691

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.00655

AC:

272

AN:

41522

American (AMR)

AF:

0.0191

AC:

292

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0294

AC:

102

AN:

3472

East Asian (EAS)

AF:

0.00193

AC:

AN:

5184

South Asian (SAS)

AF:

0.0606

AC:

292

AN:

4818

European-Finnish (FIN)

AF:

0.0188

AC:

200

AN:

10612

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0326

AC:

2220

AN:

68018

Other (OTH)

AF:

0.0256

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

173

345

518

690

863

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

138

184

230

<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:

0.0271

Hom.:

Bravo

AF:

0.0204

TwinsUK

AF:

0.0286

AC:

106

ALSPAC

AF:

0.0324

AC:

125

ESP6500AA

AF:

0.00726

AC:

ESP6500EA

AF:

0.0301

AC:

259

ExAC

AF:

0.0288

AC:

3498

Asia WGS

AF:

0.0270

AC:

AN:

3478

EpiCase

AF:

0.0316

EpiControl

AF:

0.0305

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Deficiency of ferroxidase

Pathogenic:1Benign:6

May 28, 2019

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 12, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 18, 2013

GeneReviews

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:curation

- -

Feb 01, 2017

GenePathDx, GenePath diagnostics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

25 years old, suspected case of Aceruloplasminemia. Next generation DNA sequencing ofperipheral blood sample has revealed the presence of two homozygous variants in the CP gene. The c.1652C>T variant is being classified as a â€˜Variant of Unknown Significance, likely benignâ€™, while the c.1679G>T variant is being classified as a â€˜Variant of Unknown Significance, likely pathogenicâ€™ based on available evidence in the databases and in silico mutation prediction methods. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified

Benign:4

Jun 16, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 09, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.75

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

0.060

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

.;T

Eigen

Pathogenic

0.69

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.93

.;D

MetaRNN

Benign

0.011

T;T

MetaSVM

Uncertain

0.57

PhyloP100

6.6

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-2.9

D;D

REVEL

Pathogenic

0.67

Sift

Uncertain

0.0010

D;D

Sift4G

Pathogenic

0.0010

D;D

Vest4

0.090

MPC

0.47

ClinPred

0.027

GERP RS

5.5

gMVP

0.90

Mutation Taster

=42/58

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over