NM_015692.5:c.5461G>A

Variant names:

• chr19-16893305-C-T
• rs201034139
• NM_015692.5:c.5461G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

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. 13/17 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:4
• Conservation: PhyloP100: 0.332
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• anterior segment dysgenesis 8

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015692.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPAMD8	NM_015692.5	MANE Select	c.5461G>A	p.Gly1821Arg	missense	Exon 42 of 42	NP_056507.3	Q8IZJ3-1
	CPAMD8	NR_147452.2		n.1371G>A		non_coding_transcript_exon	Exon 3 of 3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPAMD8	ENST00000443236.7	TSL:1 MANE Select	c.5461G>A	p.Gly1821Arg	missense	Exon 42 of 42	ENSP00000402505.3	Q8IZJ3-1
	CPAMD8	ENST00000942844.1		c.5425G>A	p.Gly1809Arg	missense	Exon 42 of 42	ENSP00000612903.1
	CPAMD8	ENST00000651564.2		c.*1111G>A		3_prime_UTR	Exon 42 of 42	ENSP00000498697.2	Q8IZJ3-2

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

GnomAD2 exomes AF: 0.000657 AC: 106 AN: 161256 AF XY: 0.000521

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 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

African (AFR) AF: 0.000220 AC: 7 AN: 31872

American (AMR) AF: 0.000244 AC: 9 AN: 36930

Ashkenazi Jewish (ASJ) AF: 0.000714 AC: 18 AN: 25214

East Asian (EAS) AF: 0.0000275 AC: 1 AN: 36338

South Asian (SAS) AF: 0.0000125 AC: 1 AN: 79982

European-Finnish (FIN) AF: 0.00185 AC: 85 AN: 45878

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5174

European-Non Finnish (NFE) AF: 0.00103 AC: 1112 AN: 1078204

Other (OTH) AF: 0.000502 AC: 29 AN: 57806

GnomAD4 genome AF: 0.000656 AC: 100 AN: 152328 Hom.: 0 Cov.: 33 AF XY: 0.000591 AC XY: 44 AN XY: 74488

African (AFR) AF: 0.000216 AC: 9 AN: 41578

American (AMR) AF: 0.000196 AC: 3 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00169 AC: 18 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00101 AC: 69 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000845 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

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Inborn genetic diseases (1)
-	1	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		0.33
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
Mutation Taster		=99/1	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

Other links and lift over

dbSNP: rs201034139; hg19: chr19-17004116; COSMIC: COSV108749353; COSMIC: COSV108749353;