rs56033670

Variant names:

• chr3-149182037-G-C
• rs56033670
• NM_000096.4:c.2522C>G

Variant summary

Our verdict is Benign. The variant received -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 (★★).

• 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:12
• Conservation: PhyloP100: 5.91
• Publications: 9 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 284863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 36 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000096.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CP	NM_000096.4	MANE Select	c.2522C>G	p.Thr841Arg	missense	Exon 14 of 19	NP_000087.2
	CP	NR_046371.2		n.2346C>G		non_coding_transcript_exon	Exon 13 of 18

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CP	ENST00000264613.11	TSL:1 MANE Select	c.2522C>G	p.Thr841Arg	missense	Exon 14 of 19	ENSP00000264613.6
	CP	ENST00000494544.1	TSL:1	c.1871C>G	p.Thr624Arg	missense	Exon 11 of 16	ENSP00000420545.1
	CP	ENST00000490639.5	TSL:1	n.2554C>G		non_coding_transcript_exon	Exon 14 of 17

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

GnomAD2 exomes AF: 0.00428 AC: 1076 AN: 251424 AF XY: 0.00417

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 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

African (AFR) AF: 0.00109 AC: 36 AN: 33060

American (AMR) AF: 0.00292 AC: 130 AN: 44456

Ashkenazi Jewish (ASJ) AF: 0.0254 AC: 658 AN: 25884

East Asian (EAS) AF: 0.0000256 AC: 1 AN: 38996

South Asian (SAS) AF: 0.000593 AC: 51 AN: 86016

European-Finnish (FIN) AF: 0.000587 AC: 31 AN: 52850

Middle Eastern (MID) AF: 0.0107 AC: 52 AN: 4866

European-Non Finnish (NFE) AF: 0.00548 AC: 6040 AN: 1102590

Other (OTH) AF: 0.00654 AC: 390 AN: 59590

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

African (AFR) AF: 0.00117 AC: 43 AN: 36884

American (AMR) AF: 0.00404 AC: 50 AN: 12378

Ashkenazi Jewish (ASJ) AF: 0.0256 AC: 88 AN: 3442

East Asian (EAS) AF: 0.00 AC: 0 AN: 4730

South Asian (SAS) AF: 0.000445 AC: 2 AN: 4490

European-Finnish (FIN) AF: 0.000492 AC: 4 AN: 8122

Middle Eastern (MID) AF: 0.0167 AC: 4 AN: 240

European-Non Finnish (NFE) AF: 0.00609 AC: 407 AN: 66874

Other (OTH) AF: 0.00937 AC: 18 AN: 1922

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

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Deficiency of ferroxidase (4)
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	1	CP-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Uncertain	0.66	D
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.70	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.0057	T
MetaSVM	Pathogenic	0.91	D
PhyloP100		5.9
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.59
Sift	Benign	0.38	T
Sift4G	Benign	0.27	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
Mutation Taster		=26/74	disease causing

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

Other links and lift over

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