Genetic Variant CPAMD8:c.5066-377C>G (chr19-16897042-G-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_015692.5(CPAMD8):c.5066-377C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.141 in 9,976 control chromosomes in the GnomAD database, including 216 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.36 ( 3062 hom., cov: 9)

Exomes 𝑓: 0.14 ( 216 hom. )

Failed GnomAD Quality Control

Consequence

CPAMD8
NM_015692.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -5.53

Publications

0 publications found

Variant links:

Genes affected

CPAMD8 (HGNC:23228): (C3 and PZP like alpha-2-macroglobulin domain containing 8) This gene encodes a member of the protease inhibitor I39 (alpha-2-macroglobulin) family of proteins. These proteins are important in innate and acquired immunity. The encoded protein is membrane-associated and proteolytically processed to generate two chains. Mutations in this gene cause a form of anterior segment dysgenesis, a developmental disorder of the eye. [provided by RefSeq, May 2017]

CPAMD8 Gene-Disease associations (from GenCC):

anterior segment dysgenesis 8
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)

CPAMD8 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BA1

GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.163 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015692.5. 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
	CPAMD8	NM_015692.5	MANE Select	c.5066-377C>G		intron	N/A	NP_056507.3	Q8IZJ3-1
	CPAMD8	NR_147452.2		n.-95C>G		upstream_gene	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CPAMD8	ENST00000443236.7	TSL:1 MANE Select	c.5066-377C>G	intron	N/A	ENSP00000402505.3	Q8IZJ3-1
CPAMD8	ENST00000942844.1		c.5030-377C>G	intron	N/A	ENSP00000612903.1
CPAMD8	ENST00000651564.2		c.5066-377C>G	intron	N/A	ENSP00000498697.2	Q8IZJ3-2

Frequencies

GnomAD3 genomes

AF:

0.358

AC:

21135

AN:

58984

Hom.:

3061

Cov.:

show subpopulations

Gnomad AFR

AF:

0.174

Gnomad AMI

AF:

0.473

Gnomad AMR

AF:

0.398

Gnomad ASJ

AF:

0.378

Gnomad EAS

AF:

0.113

Gnomad SAS

AF:

0.320

Gnomad FIN

AF:

0.429

Gnomad MID

AF:

0.405

Gnomad NFE

AF:

0.420

Gnomad OTH

AF:

0.360

GnomAD4 exome

AF:

0.141

AC:

1409

AN:

9976

Hom.:

216

AF XY:

0.146

AC XY:

727

AN XY:

4968

show subpopulations

African (AFR)

AF:

0.0423

AC:

AN:

568

American (AMR)

AF:

0.117

AC:

AN:

264

Ashkenazi Jewish (ASJ)

AF:

0.114

AC:

AN:

464

East Asian (EAS)

AF:

0.0160

AC:

AN:

874

South Asian (SAS)

AF:

0.169

AC:

AN:

136

European-Finnish (FIN)

AF:

0.109

AC:

AN:

470

Middle Eastern (MID)

AF:

0.161

AC:

AN:

European-Non Finnish (NFE)

AF:

0.172

AC:

1103

AN:

6426

Other (OTH)

AF:

0.140

AC:

100

AN:

712

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

147

196

245

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.358

AC:

21153

AN:

59020

Hom.:

3062

Cov.:

AF XY:

0.354

AC XY:

9637

AN XY:

27192

show subpopulations

African (AFR)

AF:

0.174

AC:

2053

AN:

11784

American (AMR)

AF:

0.398

AC:

2139

AN:

5376

Ashkenazi Jewish (ASJ)

AF:

0.378

AC:

647

AN:

1712

East Asian (EAS)

AF:

0.113

AC:

148

AN:

1308

South Asian (SAS)

AF:

0.322

AC:

481

AN:

1496

European-Finnish (FIN)

AF:

0.429

AC:

1354

AN:

3158

Middle Eastern (MID)

AF:

0.409

AC:

AN:

110

European-Non Finnish (NFE)

AF:

0.420

AC:

13810

AN:

32888

Other (OTH)

AF:

0.358

AC:

268

AN:

748

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

685

1370

2055

2740

3425

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

190

380

570

760

950

<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:

0.157

Hom.:

397

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

4.1

(source)

DANN

Benign

0.34

PhyloP100

-5.5

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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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