rs16861598

Variant names:

• chr3-149182259-C-T
• rs16861598
• NM_000096.4:c.2426-126G>A

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.2426-126G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0379 in 1,049,508 control chromosomes in the GnomAD database, including 5,872 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (3708 hom., cov: 31)
  • Exomes 𝑓: 0.023 (2164 hom.)
• Consequence: CP NM_000096.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.767
• Publications: 3 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=-0.86).
• BP6: Variant 3-149182259-C-T is Benign according to our data. Variant chr3-149182259-C-T is described in ClinVar as Benign. ClinVar VariationId is 1268348.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.415 is higher than 0.05.

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.2426-126G>A		intron	N/A	NP_000087.2
	CP	NR_046371.2		n.2250-126G>A		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CP	ENST00000264613.11	TSL:1 MANE Select	c.2426-126G>A		intron	N/A	ENSP00000264613.6
	CP	ENST00000494544.1	TSL:1	c.1775-126G>A		intron	N/A	ENSP00000420545.1
	CP	ENST00000490639.5	TSL:1	n.2458-126G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.128 AC: 19402 AN: 152020 Hom.: 3695 Cov.: 31

Gnomad AFR AF: 0.420

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0484

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00683

Gnomad FIN AF: 0.0241

Gnomad MID AF: 0.0382

Gnomad NFE AF: 0.0119

Gnomad OTH AF: 0.0850

GnomAD4 exome AF: 0.0226 AC: 20279 AN: 897372 Hom.: 2164 AF XY: 0.0205 AC XY: 9536 AN XY: 464422

African (AFR) AF: 0.426 AC: 8991 AN: 21086

American (AMR) AF: 0.0300 AC: 1130 AN: 37632

Ashkenazi Jewish (ASJ) AF: 0.00359 AC: 79 AN: 22032

East Asian (EAS) AF: 0.0000578 AC: 2 AN: 34616

South Asian (SAS) AF: 0.00680 AC: 484 AN: 71168

European-Finnish (FIN) AF: 0.0205 AC: 790 AN: 38528

Middle Eastern (MID) AF: 0.0381 AC: 158 AN: 4148

European-Non Finnish (NFE) AF: 0.0112 AC: 7012 AN: 626392

Other (OTH) AF: 0.0391 AC: 1633 AN: 41770

GnomAD4 genome AF: 0.128 AC: 19464 AN: 152136 Hom.: 3708 Cov.: 31 AF XY: 0.124 AC XY: 9201 AN XY: 74408

African (AFR) AF: 0.421 AC: 17422 AN: 41412

American (AMR) AF: 0.0482 AC: 738 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00684 AC: 33 AN: 4828

European-Finnish (FIN) AF: 0.0241 AC: 256 AN: 10606

Middle Eastern (MID) AF: 0.0377 AC: 11 AN: 292

European-Non Finnish (NFE) AF: 0.0119 AC: 812 AN: 68022

Other (OTH) AF: 0.0841 AC: 178 AN: 2116

Alfa AF: 0.0505 Hom.: 1492

Bravo AF: 0.144

Asia WGS AF: 0.0300 AC: 106 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.2
DANN	Benign	0.72
PhyloP100		-0.77
Mutation Taster		=100/0	polymorphism (auto)

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: rs16861598; hg19: chr3-148900046;