chr12-38730326-T-C

Variant names:

• chr12-38730326-T-C
• rs202081373
• NM_153634.3:c.755A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_153634.3(CPNE8):​c.755A>G​(p.Tyr252Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000208 in 1,445,046 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CPNE8 NM_153634.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.74
• Publications: 0 publications found

Genes affected

CPNE8 (HGNC:23498): (copine 8) Calcium-dependent membrane-binding proteins may regulate molecular events at the interface of the cell membrane and cytoplasm. This gene is one of several genes that encode a calcium-dependent protein containing two N-terminal type II C2 domains and an integrin A domain-like sequence in the C-terminus. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153634.3. 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
	CPNE8	NM_153634.3	MANE Select	c.755A>G	p.Tyr252Cys	missense	Exon 11 of 20	NP_705898.1	Q86YQ8-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPNE8	ENST00000331366.10	TSL:1 MANE Select	c.755A>G	p.Tyr252Cys	missense	Exon 11 of 20	ENSP00000329748.5	Q86YQ8-1
	CPNE8	ENST00000360449.3	TSL:2	c.719A>G	p.Tyr240Cys	missense	Exon 11 of 20	ENSP00000353633.3	E7ENV7
	CPNE8	ENST00000862791.1		c.755A>G	p.Tyr252Cys	missense	Exon 11 of 20	ENSP00000532850.1

Frequencies

GnomAD3 genomes AF: 0.00000664 AC: 1 AN: 150662 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000148

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000403 AC: 1 AN: 248244 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000888

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000208 AC: 3 AN: 1445046 Hom.: 0 Cov.: 26 AF XY: 0.00000278 AC XY: 2 AN XY: 719772

African (AFR) AF: 0.00 AC: 0 AN: 33102

American (AMR) AF: 0.00 AC: 0 AN: 44422

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25892

East Asian (EAS) AF: 0.00 AC: 0 AN: 39428

South Asian (SAS) AF: 0.00 AC: 0 AN: 85342

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52970

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5726

European-Non Finnish (NFE) AF: 0.00000182 AC: 2 AN: 1098444

Other (OTH) AF: 0.00 AC: 0 AN: 59720

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000663 AC: 1 AN: 150778 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 73620

African (AFR) AF: 0.00 AC: 0 AN: 41224

American (AMR) AF: 0.00 AC: 0 AN: 14988

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5074

South Asian (SAS) AF: 0.00 AC: 0 AN: 4778

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10470

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67494

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

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.094	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T
Eigen	Benign	0.063
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.025	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		4.7
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.20
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.042	D
Polyphen		0.0030	B
Vest4		0.87
MVP		0.57
MPC		1.1
ClinPred		0.95	D
GERP RS		4.4
Varity_R		0.42
gMVP		0.62
Mutation Taster		=57/43	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: rs202081373; hg19: chr12-39124128;