19-16893305-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_015692.5(CPAMD8):c.5461G>A(p.Gly1821Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000879 in 1,549,726 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00090 ( 4 hom. )

Consequence

CPAMD8
NM_015692.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 0.332

Publications

3 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: ClinGen, PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

CPAMD8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009096891).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000656 (100/152328) while in subpopulation NFE AF = 0.00101 (69/68028). AF 95% confidence interval is 0.000821. There are 0 homozygotes in GnomAd4. There are 44 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPAMD8	NM_015692.5 link	c.5461G>A	p.Gly1821Arg	missense_variant	Exon 42 of 42	ENST00000443236.7	NP_056507.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPAMD8	ENST00000443236.7 link	c.5461G>A	p.Gly1821Arg	missense_variant	Exon 42 of 42	1	NM_015692.5	ENSP00000402505.3		Q8IZJ3-1

Frequencies

GnomAD3 genomes

AF:

0.000657

AC:

100

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00169

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00101

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000657

AC:

106

AN:

161256

AF XY:

0.000521

show subpopulations

Gnomad AFR exome

AF:

0.000457

Gnomad AMR exome

AF:

0.000194

Gnomad ASJ exome

AF:

0.000699

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00210

Gnomad NFE exome

AF:

0.000941

Gnomad OTH exome

AF:

0.000224

GnomAD4 exome

AF:

0.000903

AC:

1262

AN:

1397398

Hom.:

Cov.:

AF XY:

0.000871

AC XY:

600

AN XY:

688660

show subpopulations

African (AFR)

AF:

0.000220

AC:

AN:

31872

American (AMR)

AF:

0.000244

AC:

AN:

36930

Ashkenazi Jewish (ASJ)

AF:

0.000714

AC:

AN:

25214

East Asian (EAS)

AF:

0.0000275

AC:

AN:

36338

South Asian (SAS)

AF:

0.0000125

AC:

AN:

79982

European-Finnish (FIN)

AF:

0.00185

AC:

AN:

45878

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5174

European-Non Finnish (NFE)

AF:

0.00103

AC:

1112

AN:

1078204

Other (OTH)

AF:

0.000502

AC:

AN:

57806

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

122

184

245

306

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

168

210

<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:

0.000656

AC:

100

AN:

152328

Hom.:

Cov.:

AF XY:

0.000591

AC XY:

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.000216

AC:

AN:

41578

American (AMR)

AF:

0.000196

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00169

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00101

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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

Alfa

AF:

0.000845

Hom.:

Bravo

AF:

0.000548

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000263

AC:

ESP6500EA

AF:

0.000244

AC:

ExAC

AF:

0.000477

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

May 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1868 of the CPAMD8 protein (p.Gly1868Arg). This variant is present in population databases (rs201034139, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with CPAMD8-related conditions. ClinVar contains an entry for this variant (Variation ID: 1438628). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Jan 08, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Has not been previously published in association with a CPAMD8-related disorder to our knowledge; In silico analysis does not support a benign or deleterious effect of this variant on protein structure/function; This variant is associated with the following publications: (PMID: 26740555) -

Inborn genetic diseases

Uncertain:1

Sep 01, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.5602G>A (p.G1868R) alteration is located in exon 42 (coding exon 42) of the CPAMD8 gene. This alteration results from a G to A substitution at nucleotide position 5602, causing the glycine (G) at amino acid position 1868 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

See cases

Uncertain:1

Sep 09, 2022

Institute of Human Genetics, University Hospital Muenster

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG categories: PM2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.53

CADD

Benign

2.8

(source)

DANN

Benign

0.76

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.089

LIST_S2

Benign

0.42

M_CAP

Benign

0.0040

MetaRNN

Benign

0.0091

MetaSVM

Benign

-1.0

PhyloP100

0.33

PrimateAI

Benign

0.45

Sift4G

Uncertain

0.038

Vest4

0.20

MVP

0.12

MPC

0.077

ClinPred

0.020

GERP RS

0.36

Mutation Taster

=99/1

polymorphism

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over