19-16896552-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015692.5(CPAMD8):c.5179G>A(p.Asp1727Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00855 in 1,502,024 control chromosomes in the GnomAD database, including 535 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.035 (261 hom., cov: 31)
  • Exomes 𝑓: 0.0056 (274 hom.)
• Consequence: CPAMD8 NM_015692.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.932

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016382039).
• BP6: Variant 19-16896552-C-T is Benign according to our data. Variant chr19-16896552-C-T is described in ClinVar as [Benign]. Clinvar id is 1248916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-16896552-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.105 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPAMD8	NM_015692.5	c.5179G>A	p.Asp1727Asn	missense_variant	40/42	ENST00000443236.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPAMD8	ENST00000443236.7	c.5179G>A	p.Asp1727Asn	missense_variant	40/42	1	NM_015692.5	P2

Frequencies

GnomAD3 genomes AF: 0.0348 AC: 5296 AN: 152104 Hom.: 259 Cov.: 31

Gnomad AFR AF: 0.108

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0206

Gnomad ASJ AF: 0.0210

Gnomad EAS AF: 0.0523

Gnomad SAS AF: 0.00497

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.0223

Gnomad NFE AF: 0.00115

Gnomad OTH AF: 0.0311

GnomAD3 exomes AF: 0.0137 AC: 1404 AN: 102614 Hom.: 49 AF XY: 0.0121 AC XY: 689 AN XY: 57048

Gnomad AFR exome AF: 0.143

Gnomad AMR exome AF: 0.0113

Gnomad ASJ exome AF: 0.0203

Gnomad EAS exome AF: 0.0661

Gnomad SAS exome AF: 0.00409

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00188

Gnomad OTH exome AF: 0.00866

GnomAD4 exome AF: 0.00558 AC: 7533 AN: 1349812 Hom.: 274 Cov.: 32 AF XY: 0.00516 AC XY: 3432 AN XY: 665168

Gnomad4 AFR exome AF: 0.114

Gnomad4 AMR exome AF: 0.0126

Gnomad4 ASJ exome AF: 0.0226

Gnomad4 EAS exome AF: 0.0444

Gnomad4 SAS exome AF: 0.00427

Gnomad4 FIN exome AF: 0.0000304

Gnomad4 NFE exome AF: 0.000677

Gnomad4 OTH exome AF: 0.0138

GnomAD4 genome AF: 0.0349 AC: 5308 AN: 152212 Hom.: 261 Cov.: 31 AF XY: 0.0335 AC XY: 2492 AN XY: 74416

Gnomad4 AFR AF: 0.108

Gnomad4 AMR AF: 0.0205

Gnomad4 ASJ AF: 0.0210

Gnomad4 EAS AF: 0.0526

Gnomad4 SAS AF: 0.00518

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00115

Gnomad4 OTH AF: 0.0307

Alfa AF: 0.00390 Hom.: 2

Bravo AF: 0.0406

ExAC AF: 0.00641 AC: 139

Asia WGS AF: 0.0240 AC: 84 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 11, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.73
Cadd	Benign	15
Dann	Uncertain	0.98
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.85	T;T
MetaRNN	Benign	0.0016	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.91	N
PrimateAI	Pathogenic	0.83	D
Sift4G	Benign	0.29	T;.
Vest4		0.15
MPC		1.3
ClinPred		0.017	T
GERP RS		1.1

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: rs10418195; hg19: chr19-17007363;