chr19-16893221-C-A

Variant names:

• chr19-16893221-C-A
• rs186748601
• NM_015692.5:c.5545G>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_015692.5(CPAMD8):​c.5545G>T​(p.Val1849Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000415 in 1,589,418 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: CPAMD8 NM_015692.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.202

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

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.020785987).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000236 (36/152366) while in subpopulation AMR AF = 0.00189 (29/15314). AF 95% confidence interval is 0.00135. There are 0 homozygotes in GnomAd4. There are 11 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position FAILED quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPAMD8	NM_015692.5	c.5545G>T	p.Val1849Leu	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	c.5545G>T	p.Val1849Leu	missense_variant	Exon 42 of 42	1	NM_015692.5	ENSP00000402505.3

Frequencies

GnomAD3 genomes AF: 0.000236 AC: 36 AN: 152248 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.0000294 AC: 6 AN: 204200 AF XY: 0.0000180

Gnomad AFR exome AF: 0.0000858

Gnomad AMR exome AF: 0.0000967

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000384

GnomAD4 exome AF: 0.0000209 AC: 30 AN: 1437052 Hom.: 0 Cov.: 30 AF XY: 0.00000841 AC XY: 6 AN XY: 713224

Gnomad4 AFR exome AF: 0.0000609 AC: 2 AN: 32838

Gnomad4 AMR exome AF: 0.000331 AC: 14 AN: 42248

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 25632

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 38612

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 83268

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 51186

Gnomad4 NFE exome AF: 0.00 AC: 0 AN: 1098234

Gnomad4 Remaining exome AF: 0.000236 AC: 14 AN: 59306

GnomAD4 genome AF: 0.000236 AC: 36 AN: 152366 Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11 AN XY: 74506

Gnomad4 AFR AF: 0.0000962 AC: 0.0000961723 AN: 0.0000961723

Gnomad4 AMR AF: 0.00189 AC: 0.00189369 AN: 0.00189369

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.00 AC: 0 AN: 0

Gnomad4 OTH AF: 0.00142 AC: 0.00141911 AN: 0.00141911

Alfa AF: 0.000254 Hom.: 0

Bravo AF: 0.000578

ExAC AF: 0.00000834 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Aug 05, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1896 of the CPAMD8 protein (p.Val1896Leu). This variant is present in population databases (rs186748601, gnomAD 0.02%). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.52
DANN	Benign	0.64
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.063	N
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.021	T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.39	T
Sift4G	Benign	0.080	T
Vest4		0.10
MVP		0.067
MPC		0.059
ClinPred		0.0082	T
GERP RS		-0.54
Mutation Taster		=100/0	polymorphism

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: rs186748601; hg19: chr19-17004032;