rs56033670

chr3-149182037-G-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000096.4(CP):c.2522C>G(p.Thr841Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00504 in 1,588,296 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0044 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0051 (36 hom.)
• Consequence: CP NM_000096.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 5.91

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005704552).
• BP6: Variant 3-149182037-G-C is Benign according to our data. Variant chr3-149182037-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 284863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-149182037-G-C is described in Lovd as [Likely_benign]. Variant chr3-149182037-G-C is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAdExome at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CP	NM_000096.4	c.2522C>G	p.Thr841Arg	missense_variant	14/19	ENST00000264613.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CP	ENST00000264613.11	c.2522C>G	p.Thr841Arg	missense_variant	14/19	1	NM_000096.4	P1
CP	ENST00000494544.1	c.1871C>G	p.Thr624Arg	missense_variant	11/16	1
CP	ENST00000490639.5	n.2554C>G		non_coding_transcript_exon_variant	14/17	1
CP	ENST00000481169.5	c.2309C>G	p.Thr770Arg	missense_variant, NMD_transcript_variant	13/18	2

Frequencies

GnomAD3 genomes AF: 0.00440 AC: 616 AN: 139914 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00117

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00405

Gnomad ASJ AF: 0.0256

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000444

Gnomad FIN AF: 0.000492

Gnomad MID AF: 0.0155

Gnomad NFE AF: 0.00609

Gnomad OTH AF: 0.00943

GnomAD3 exomes AF: 0.00428 AC: 1076 AN: 251424 Hom.: 10 AF XY: 0.00417 AC XY: 566 AN XY: 135876

Gnomad AFR exome AF: 0.00135

Gnomad AMR exome AF: 0.00278

Gnomad ASJ exome AF: 0.0258

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000523

Gnomad FIN exome AF: 0.000647

Gnomad NFE exome AF: 0.00544

Gnomad OTH exome AF: 0.00782

GnomAD4 exome AF: 0.00510 AC: 7389 AN: 1448308 Hom.: 36 Cov.: 35 AF XY: 0.00506 AC XY: 3645 AN XY: 720516

Gnomad4 AFR exome AF: 0.00109

Gnomad4 AMR exome AF: 0.00292

Gnomad4 ASJ exome AF: 0.0254

Gnomad4 EAS exome AF: 0.0000256

Gnomad4 SAS exome AF: 0.000593

Gnomad4 FIN exome AF: 0.000587

Gnomad4 NFE exome AF: 0.00548

Gnomad4 OTH exome AF: 0.00654

GnomAD4 genome AF: 0.00440 AC: 616 AN: 139988 Hom.: 0 Cov.: 30 AF XY: 0.00401 AC XY: 268 AN XY: 66866

Gnomad4 AFR AF: 0.00117

Gnomad4 AMR AF: 0.00404

Gnomad4 ASJ AF: 0.0256

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000445

Gnomad4 FIN AF: 0.000492

Gnomad4 NFE AF: 0.00609

Gnomad4 OTH AF: 0.00937

Alfa AF: 0.00658 Hom.: 1

Bravo AF: 0.00410

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00623 AC: 24

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00616 AC: 53

ExAC AF: 0.00381 AC: 463

EpiCase AF: 0.00731

EpiControl AF: 0.00676

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	CP: BS2 -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 21, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 28, 2016	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Deficiency of ferroxidase Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 03, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 21, 2024	- -

CP-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 26, 2021

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	0.21
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.44
Cadd	Benign	21
Dann	Benign	0.96
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.0057	T;T
MetaSVM	Pathogenic	0.91	D
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-2.4	N;N
REVEL	Uncertain	0.59
Sift	Benign	0.38	T;T
Sift4G	Benign	0.27	T;T
Vest4		0.88
MVP		0.97
MPC		0.23
ClinPred		0.047	T
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.85

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

LitVar

Other links and lift over

dbSNP: rs56033670; hg19: chr3-148899824; COSMIC: COSV52830669; COSMIC: COSV52830669;