19-16970892-T-TG

Variant names:

• chr19-16970892-T-TG
• rs756064750
• NM_015692.5:c.2211dupC

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 1.40
• 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: ClinGen, PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	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: 20 AN: 152150 Hom.: 0 Cov.: 31

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: 21 AN: 244390 AF XY: 0.0000675

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.: 0 Cov.: 31 AF XY: 0.000171 AC XY: 124 AN XY: 726634

African (AFR) AF: 0.0000898 AC: 3 AN: 33410

American (AMR) AF: 0.00 AC: 0 AN: 44440

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26082

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39674

South Asian (SAS) AF: 0.0000928 AC: 8 AN: 86194

European-Finnish (FIN) AF: 0.000339 AC: 18 AN: 53132

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.000194 AC: 216 AN: 1111578

Other (OTH) AF: 0.000116 AC: 7 AN: 60344

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152150 Hom.: 0 Cov.: 31 AF XY: 0.000161 AC XY: 12 AN XY: 74308

African (AFR) AF: 0.000241 AC: 10 AN: 41434

American (AMR) AF: 0.00 AC: 0 AN: 15270

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000217 Hom.: 0

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

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
1	-	-	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)

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: rs756064750; hg19: chr19-17081702; COSMIC: COSV52231889;