19-16893238-T-C

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.5528A>G(p.Gln1843Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.321 in 1,578,602 control chromosomes in the GnomAD database, including 84,483 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.27 (6377 hom., cov: 33)
  • Exomes 𝑓: 0.33 (78106 hom.)
• Consequence: CPAMD8 NM_015692.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.50

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=8.649528E-4).
• BP6: Variant 19-16893238-T-C is Benign according to our data. Variant chr19-16893238-T-C is described in ClinVar as [Benign]. Clinvar id is 1237649.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.339 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPAMD8	NM_015692.5	c.5528A>G	p.Gln1843Arg	missense_variant	42/42	ENST00000443236.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPAMD8	ENST00000443236.7	c.5528A>G	p.Gln1843Arg	missense_variant	42/42	1	NM_015692.5	P2

Frequencies

GnomAD3 genomes AF: 0.271 AC: 41274 AN: 152132 Hom.: 6368 Cov.: 33

Gnomad AFR AF: 0.132

Gnomad AMI AF: 0.415

Gnomad AMR AF: 0.293

Gnomad ASJ AF: 0.291

Gnomad EAS AF: 0.136

Gnomad SAS AF: 0.268

Gnomad FIN AF: 0.371

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.343

Gnomad OTH AF: 0.302

GnomAD3 exomes AF: 0.297 AC: 56834 AN: 191656 Hom.: 8832 AF XY: 0.303 AC XY: 31488 AN XY: 103922

Gnomad AFR exome AF: 0.124

Gnomad AMR exome AF: 0.278

Gnomad ASJ exome AF: 0.285

Gnomad EAS exome AF: 0.134

Gnomad SAS exome AF: 0.285

Gnomad FIN exome AF: 0.367

Gnomad NFE exome AF: 0.345

Gnomad OTH exome AF: 0.311

GnomAD4 exome AF: 0.327 AC: 465708 AN: 1426352 Hom.: 78106 Cov.: 32 AF XY: 0.325 AC XY: 229943 AN XY: 706492

Gnomad4 AFR exome AF: 0.117

Gnomad4 AMR exome AF: 0.274

Gnomad4 ASJ exome AF: 0.286

Gnomad4 EAS exome AF: 0.160

Gnomad4 SAS exome AF: 0.284

Gnomad4 FIN exome AF: 0.362

Gnomad4 NFE exome AF: 0.344

Gnomad4 OTH exome AF: 0.306

GnomAD4 genome AF: 0.271 AC: 41321 AN: 152250 Hom.: 6377 Cov.: 33 AF XY: 0.272 AC XY: 20278 AN XY: 74432

Gnomad4 AFR AF: 0.132

Gnomad4 AMR AF: 0.293

Gnomad4 ASJ AF: 0.291

Gnomad4 EAS AF: 0.137

Gnomad4 SAS AF: 0.269

Gnomad4 FIN AF: 0.371

Gnomad4 NFE AF: 0.343

Gnomad4 OTH AF: 0.299

Alfa AF: 0.327 Hom.: 4356

Bravo AF: 0.261

TwinsUK AF: 0.349 AC: 1295

ALSPAC AF: 0.336 AC: 1296

ESP6500AA AF: 0.133 AC: 493

ESP6500EA AF: 0.330 AC: 2683

ExAC AF: 0.261 AC: 30840

Asia WGS AF: 0.202 AC: 704 AN: 3478

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 29, 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	0.074
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.80
Cadd	Benign	0.0090
Dann	Benign	0.23
Eigen	Benign	-1.8
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.16	T
MetaRNN	Benign	0.00086	T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.28	T
Sift4G	Benign	0.51	T
Vest4		0.016
MPC		0.063
ClinPred		0.0021	T
GERP RS		-1.7

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: rs1054533; hg19: chr19-17004049; COSMIC: COSV50185573; COSMIC: COSV50185573;