rs16861582

Variant names:

• chr3-149178643-A-G
• rs16861582
• NM_000096.4:c.2662-12T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000096.4(CP):​c.2662-12T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.295 in 1,573,888 control chromosomes in the GnomAD database, including 70,259 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (8898 hom., cov: 32)
  • Exomes 𝑓: 0.29 (61361 hom.)
• Consequence: CP NM_000096.4 intron
• Scores: Splicing: ADA: 0.0001142
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.693
• Publications: 18 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 3-149178643-A-G is Benign according to our data. Variant chr3-149178643-A-G is described in ClinVar as Benign. ClinVar VariationId is 194589.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.431 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CP	NM_000096.4	c.2662-12T>C		intron_variant	Intron 15 of 18	ENST00000264613.11	NP_000087.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CP	ENST00000264613.11	c.2662-12T>C		intron_variant	Intron 15 of 18	1	NM_000096.4	ENSP00000264613.6

Frequencies

GnomAD3 genomes AF: 0.330 AC: 50126 AN: 151884 Hom.: 8889 Cov.: 32

Gnomad AFR AF: 0.436

Gnomad AMI AF: 0.311

Gnomad AMR AF: 0.241

Gnomad ASJ AF: 0.178

Gnomad EAS AF: 0.366

Gnomad SAS AF: 0.295

Gnomad FIN AF: 0.388

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.286

Gnomad OTH AF: 0.286

GnomAD2 exomes AF: 0.295 AC: 71017 AN: 241012 AF XY: 0.294

Gnomad AFR exome AF: 0.445

Gnomad AMR exome AF: 0.208

Gnomad ASJ exome AF: 0.182

Gnomad EAS exome AF: 0.368

Gnomad FIN exome AF: 0.372

Gnomad NFE exome AF: 0.286

Gnomad OTH exome AF: 0.270

GnomAD4 exome AF: 0.291 AC: 413383 AN: 1421886 Hom.: 61361 Cov.: 26 AF XY: 0.290 AC XY: 205778 AN XY: 709336

African (AFR) AF: 0.449 AC: 14634 AN: 32600

American (AMR) AF: 0.213 AC: 9423 AN: 44226

Ashkenazi Jewish (ASJ) AF: 0.183 AC: 4727 AN: 25794

East Asian (EAS) AF: 0.360 AC: 14131 AN: 39244

South Asian (SAS) AF: 0.289 AC: 24534 AN: 84770

European-Finnish (FIN) AF: 0.363 AC: 18942 AN: 52222

Middle Eastern (MID) AF: 0.191 AC: 1089 AN: 5698

European-Non Finnish (NFE) AF: 0.287 AC: 308961 AN: 1078326

Other (OTH) AF: 0.287 AC: 16942 AN: 59006

GnomAD4 genome AF: 0.330 AC: 50180 AN: 152002 Hom.: 8898 Cov.: 32 AF XY: 0.332 AC XY: 24671 AN XY: 74300

African (AFR) AF: 0.436 AC: 18078 AN: 41456

American (AMR) AF: 0.241 AC: 3681 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.178 AC: 617 AN: 3464

East Asian (EAS) AF: 0.367 AC: 1891 AN: 5158

South Asian (SAS) AF: 0.296 AC: 1421 AN: 4804

European-Finnish (FIN) AF: 0.388 AC: 4102 AN: 10574

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.286 AC: 19442 AN: 67970

Other (OTH) AF: 0.284 AC: 600 AN: 2114

Alfa AF: 0.294 Hom.: 7192

Bravo AF: 0.327

Asia WGS AF: 0.335 AC: 1164 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 21, 2015

Eurofins Ntd Llc (ga)

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

- -

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Deficiency of ferroxidase Benign:2

Jan 12, 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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Jul 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.2
DANN	Benign	0.57
PhyloP100		0.69
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00011
dbscSNV1_RF	Benign	0.0040
SpliceAI score (max)		0.020		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: rs16861582; hg19: chr3-148896430;