19-16893305-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.332

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPAMD8	NM_015692.5	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	c.5461G>A	p.Gly1821Arg	missense_variant	42/42	1	NM_015692.5	P2

Frequencies

GnomAD3 genomes AF: 0.000657 AC: 100 AN: 152210 Hom.: 0 Cov.: 33

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.: 1 AF XY: 0.000521 AC XY: 45 AN XY: 86348

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.: 4 Cov.: 31 AF XY: 0.000871 AC XY: 600 AN XY: 688660

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.: 0 Cov.: 33 AF XY: 0.000591 AC XY: 44 AN XY: 74488

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.: 0

Bravo AF: 0.000548

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000263 AC: 1

ESP6500EA AF: 0.000244 AC: 2

ExAC AF: 0.000477 AC: 55

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

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

Invitae

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	T
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	N
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.0091	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.45	T
Sift4G	Uncertain	0.038	D
Vest4		0.20
MVP		0.12
MPC		0.077
ClinPred		0.020	T
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

Other links and lift over

dbSNP: rs201034139; hg19: chr19-17004116;