NM_015692.5:c.5349G>A

Variant names:

• chr19-16896253-C-T
• rs201195391
• NM_015692.5:c.5349G>A

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_015692.5(CPAMD8):​c.5349G>A​(p.Gln1783Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00213 in 1,613,650 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0022 (6 hom.)
• Consequence: CPAMD8 NM_015692.5 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.178
• 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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.011).
• BP6: Variant 19-16896253-C-T is Benign according to our data. Variant chr19-16896253-C-T is described in ClinVar as Benign. ClinVar VariationId is 1529514.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.178 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00173 (264/152238) while in subpopulation NFE AF = 0.0026 (177/68006). AF 95% confidence interval is 0.00229. There are 0 homozygotes in GnomAd4. There are 138 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 6 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.5349G>A	p.Gln1783Gln	synonymous	Exon 41 of 42	NP_056507.3	Q8IZJ3-1
	CPAMD8	NR_147452.2		n.161G>A		non_coding_transcript_exon	Exon 2 of 3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPAMD8	ENST00000443236.7	TSL:1 MANE Select	c.5349G>A	p.Gln1783Gln	synonymous	Exon 41 of 42	ENSP00000402505.3	Q8IZJ3-1
	CPAMD8	ENST00000942844.1		c.5313G>A	p.Gln1771Gln	synonymous	Exon 41 of 42	ENSP00000612903.1
	CPAMD8	ENST00000651564.2		c.5349G>A	p.Gln1783Gln	synonymous	Exon 41 of 42	ENSP00000498697.2	Q8IZJ3-2

Frequencies

GnomAD3 genomes AF: 0.00174 AC: 264 AN: 152122 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00669

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00260

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.00224 AC: 556 AN: 248538 AF XY: 0.00217

Gnomad AFR exome AF: 0.000260

Gnomad AMR exome AF: 0.0000870

Gnomad ASJ exome AF: 0.000399

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00724

Gnomad NFE exome AF: 0.00341

Gnomad OTH exome AF: 0.000828

GnomAD4 exome AF: 0.00217 AC: 3176 AN: 1461412 Hom.: 6 Cov.: 32 AF XY: 0.00211 AC XY: 1532 AN XY: 727020

African (AFR) AF: 0.000418 AC: 14 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.000804 AC: 21 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86256

European-Finnish (FIN) AF: 0.00623 AC: 330 AN: 52964

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00246 AC: 2732 AN: 1112000

Other (OTH) AF: 0.00119 AC: 72 AN: 60392

GnomAD4 genome AF: 0.00173 AC: 264 AN: 152238 Hom.: 0 Cov.: 31 AF XY: 0.00185 AC XY: 138 AN XY: 74432

African (AFR) AF: 0.000168 AC: 7 AN: 41546

American (AMR) AF: 0.000262 AC: 4 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00669 AC: 71 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00260 AC: 177 AN: 68006

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.00193 Hom.: 0

Bravo AF: 0.00129

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000514 AC: 2

ESP6500EA AF: 0.00349 AC: 29

ExAC AF: 0.00251 AC: 303

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	CPAMD8-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	8.7
DANN	Benign	0.78
Eigen	Benign	-0.94
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.049	N
PhyloP100		0.18
ClinPred		0.0050	T
GERP RS		1.1
PromoterAI		0.044	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs201195391; hg19: chr19-17007064;