19-16893305-C-T

Position:

chr19-16893305-C-T

Variant summary

Our verdict is Benign. Variant got -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. 12/16 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:3

Conservation

PhyloP100: 0.332

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. 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/exons	MANE	UniProt
CPAMD8	NM_015692.5 linkuse as main transcript	c.5461G>A	p.Gly1821Arg	missense_variant	42/42	ENST00000443236.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPAMD8	ENST00000443236.7 linkuse as main transcript	c.5461G>A	p.Gly1821Arg	missense_variant	42/42	1	NM_015692.5	P2	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

GnomAD3 exomes

AF:

0.000657

AC:

106

AN:

161256

Hom.:

AF XY:

0.000521

AC XY:

AN XY:

86348

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 SAS exome

AF:

0.0000424

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

Gnomad4 AFR exome

AF:

0.000220

Gnomad4 AMR exome

AF:

0.000244

Gnomad4 ASJ exome

AF:

0.000714

Gnomad4 EAS exome

AF:

0.0000275

Gnomad4 SAS exome

AF:

0.0000125

Gnomad4 FIN exome

AF:

0.00185

Gnomad4 NFE exome

AF:

0.00103

Gnomad4 OTH exome

AF:

0.000502

GnomAD4 genome

AF:

0.000656

AC:

100

AN:

152328

Hom.:

Cov.:

AF XY:

0.000591

AC XY:

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.000216

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00169

Gnomad4 NFE

AF:

0.00101

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000864

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:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 01, 2021

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

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Sep 09, 2022

ACMG categories: PM2 -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 12, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest 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. -

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

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

MutationTaster

Benign

1.0

PrimateAI

Benign

0.45

Sift4G

Uncertain

0.038

Vest4

0.20

MVP

0.12

MPC

0.077

ClinPred

0.020

GERP RS

0.36

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over