Genetic Variant NM_015692.5:c.2211dupC (chr19-16970892-T-TG) – ACMG Classification: Pathogenic (16 pts)

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_015692.5(CPAMD8):c.2211dupC(p.Arg738GlnfsTer23) variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00017 in 1,612,758 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

CPAMD8
NM_015692.5 frameshift, splice_region

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 1.40

Publications

3 publications found

Variant links:

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: ClinGen, PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

CPAMD8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 19-16970892-T-TG is Pathogenic according to our data. Variant chr19-16970892-T-TG is described in ClinVar as Pathogenic. ClinVar VariationId is 375310.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.2211dupC	p.Arg738GlnfsTer23	frameshift splice_region	Exon 18 of 42	NP_056507.3
	CPAMD8	NR_165644.1		n.1747dupC		splice_region non_coding_transcript_exon	Exon 14 of 15

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CPAMD8	ENST00000443236.7	TSL:1 MANE Select	c.2211dupC	p.Arg738GlnfsTer23	frameshift splice_region	Exon 18 of 42	ENSP00000402505.3
CPAMD8	ENST00000291440.4	TSL:1	n.*67dupC		splice_region non_coding_transcript_exon	Exon 14 of 15	ENSP00000291440.4
CPAMD8	ENST00000291440.4	TSL:1	n.*67dupC		3_prime_UTR	Exon 14 of 15	ENSP00000291440.4

Frequencies

GnomAD3 genomes

AF:

0.000131

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000859

AC:

AN:

244390

AF XY:

0.0000675

show subpopulations

Gnomad AFR exome

AF:

0.0000662

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000101

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000144

Gnomad OTH exome

AF:

0.000168

GnomAD4 exome

AF:

0.000174

AC:

254

AN:

1460608

Hom.:

Cov.:

AF XY:

0.000171

AC XY:

124

AN XY:

726634

show subpopulations

African (AFR)

AF:

0.0000898

AC:

AN:

33410

American (AMR)

AF:

0.00

AC:

AN:

44440

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26082

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39674

South Asian (SAS)

AF:

0.0000928

AC:

AN:

86194

European-Finnish (FIN)

AF:

0.000339

AC:

AN:

53132

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.000194

AC:

216

AN:

1111578

Other (OTH)

AF:

0.000116

AC:

AN:

60344

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000131

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74308

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41434

American (AMR)

AF:

0.00

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000217

Hom.:

Bravo

AF:

0.0000982

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000595

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Anterior segment dysgenesis 8 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.4

Mutation Taster

=25/175

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over