rs914146997

Variant names:

• chr12-38762205-C-A
• rs914146997
• NM_153634.3:c.587G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_153634.3(CPNE8):​c.587G>T​(p.Cys196Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CPNE8 NM_153634.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.82
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.856

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.587G>T	p.Cys196Phe	missense	Exon 9 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.587G>T	p.Cys196Phe	missense	Exon 9 of 20	ENSP00000329748.5	Q86YQ8-1
	CPNE8	ENST00000360449.3	TSL:2	c.551G>T	p.Cys184Phe	missense	Exon 9 of 20	ENSP00000353633.3	E7ENV7
	CPNE8	ENST00000862791.1		c.587G>T	p.Cys196Phe	missense	Exon 9 of 20	ENSP00000532850.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1428210 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 711156

African (AFR) AF: 0.00 AC: 0 AN: 32142

American (AMR) AF: 0.00 AC: 0 AN: 40662

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25346

East Asian (EAS) AF: 0.00 AC: 0 AN: 39014

South Asian (SAS) AF: 0.00 AC: 0 AN: 81868

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52724

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5652

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1091696

Other (OTH) AF: 0.00 AC: 0 AN: 59106

GnomAD4 genome Cov.: 33

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	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.33	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	-0.015	N
PhyloP100		5.8
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-4.9	D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.62		Loss of sheet (P = 0.0817)
MVP		0.74
MPC		1.4
ClinPred		0.99	D
GERP RS		3.9
Varity_R		0.56
gMVP		0.68
Mutation Taster		=48/52	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs914146997; hg19: chr12-39156007;