dbSNP rs16861582: CP:c.2662-12T>C (chr3-149178643-A-G) – ACMG Classification: Benign (-20 pts)

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.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

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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen, Ambry Genetics, Orphanet
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 (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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CP	NM_000096.4	MANE Select	c.2662-12T>C		intron	N/A	NP_000087.2	P00450
	CP	NR_046371.2		n.2486-12T>C		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CP	ENST00000264613.11	TSL:1 MANE Select	c.2662-12T>C	intron	N/A	ENSP00000264613.6	P00450
CP	ENST00000494544.1	TSL:1	c.2011-12T>C	intron	N/A	ENSP00000420545.1	H7C5R1
CP	ENST00000460674.5	TSL:1	n.579-12T>C	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.330

AC:

50126

AN:

151884

Hom.:

8889

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.290

AC XY:

205778

AN XY:

709336

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

13469

26938

40408

53877

67346

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10212

20424

30636

40848

51060

<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:

0.330

AC:

50180

AN:

152002

Hom.:

8898

Cov.:

AF XY:

0.332

AC XY:

24671

AN XY:

74300

show subpopulations

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:

AN:

294

European-Non Finnish (NFE)

AF:

0.286

AC:

19442

AN:

67970

Other (OTH)

AF:

0.284

AC:

600

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1650

3300

4949

6599

8249

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

494

988

1482

1976

2470

<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:

0.294

Hom.:

7192

Bravo

AF:

0.327

Asia WGS

AF:

0.335

AC:

1164

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

Deficiency of ferroxidase (2)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

5.2

(source)

DANN

Benign

0.57

PhyloP100

0.69

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over