19-16895976-G-A

Variant names:

• chr19-16895976-G-A
• rs2227367
• NM_015692.5:c.5426+200C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015692.5(CPAMD8):​c.5426+200C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.291 in 704,508 control chromosomes in the GnomAD database, including 32,803 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5982 hom., cov: 28)
  • Exomes 𝑓: 0.30 (26821 hom.)
• Consequence: CPAMD8 NM_015692.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0160
• Publications: 1 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 19-16895976-G-A is Benign according to our data. Variant chr19-16895976-G-A is described in ClinVar as Benign. ClinVar VariationId is 1278790.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.334 is higher than 0.05.

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.5426+200C>T		intron	N/A	NP_056507.3	Q8IZJ3-1
	CPAMD8	NR_147452.2		n.238+200C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPAMD8	ENST00000443236.7	TSL:1 MANE Select	c.5426+200C>T		intron	N/A	ENSP00000402505.3	Q8IZJ3-1
	CPAMD8	ENST00000942844.1		c.5390+200C>T		intron	N/A	ENSP00000612903.1
	CPAMD8	ENST00000651564.2		c.5426+200C>T		intron	N/A	ENSP00000498697.2	Q8IZJ3-2

Frequencies

GnomAD3 genomes AF: 0.259 AC: 39187 AN: 151126 Hom.: 5979 Cov.: 28

Gnomad AFR AF: 0.113

Gnomad AMI AF: 0.415

Gnomad AMR AF: 0.290

Gnomad ASJ AF: 0.290

Gnomad EAS AF: 0.0606

Gnomad SAS AF: 0.256

Gnomad FIN AF: 0.352

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.338

Gnomad OTH AF: 0.293

GnomAD2 exomes AF: 0.279 AC: 37562 AN: 134512 AF XY: 0.285

Gnomad AFR exome AF: 0.101

Gnomad AMR exome AF: 0.275

Gnomad ASJ exome AF: 0.284

Gnomad EAS exome AF: 0.0630

Gnomad FIN exome AF: 0.353

Gnomad NFE exome AF: 0.340

Gnomad OTH exome AF: 0.305

GnomAD4 exome AF: 0.300 AC: 165980 AN: 553264 Hom.: 26821 Cov.: 5 AF XY: 0.301 AC XY: 90112 AN XY: 299592

African (AFR) AF: 0.106 AC: 1693 AN: 15948

American (AMR) AF: 0.272 AC: 9371 AN: 34440

Ashkenazi Jewish (ASJ) AF: 0.282 AC: 5570 AN: 19784

East Asian (EAS) AF: 0.0681 AC: 2166 AN: 31814

South Asian (SAS) AF: 0.275 AC: 17255 AN: 62666

European-Finnish (FIN) AF: 0.339 AC: 11007 AN: 32424

Middle Eastern (MID) AF: 0.285 AC: 933 AN: 3276

European-Non Finnish (NFE) AF: 0.339 AC: 109238 AN: 322616

Other (OTH) AF: 0.289 AC: 8747 AN: 30296

GnomAD4 genome AF: 0.259 AC: 39216 AN: 151244 Hom.: 5982 Cov.: 28 AF XY: 0.259 AC XY: 19132 AN XY: 73846

African (AFR) AF: 0.113 AC: 4667 AN: 41330

American (AMR) AF: 0.290 AC: 4408 AN: 15212

Ashkenazi Jewish (ASJ) AF: 0.290 AC: 1006 AN: 3470

East Asian (EAS) AF: 0.0609 AC: 310 AN: 5088

South Asian (SAS) AF: 0.257 AC: 1236 AN: 4806

European-Finnish (FIN) AF: 0.352 AC: 3658 AN: 10398

Middle Eastern (MID) AF: 0.320 AC: 94 AN: 294

European-Non Finnish (NFE) AF: 0.338 AC: 22854 AN: 67642

Other (OTH) AF: 0.289 AC: 606 AN: 2096

Alfa AF: 0.296 Hom.: 1476

Bravo AF: 0.251

Asia WGS AF: 0.166 AC: 578 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.8
DANN	Benign	0.92
PhyloP100		-0.016
PromoterAI		-0.098	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs2227367; hg19: chr19-17006787;