rs750050507

Variant names:

• chr12-38767713-G-A
• rs750050507
• NM_153634.3:c.497C>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_153634.3(CPNE8):​c.497C>T​(p.Ala166Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000573 in 1,395,768 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000057 (0 hom.)
• Consequence: CPNE8 NM_153634.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.92

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

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.847

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPNE8	NM_153634.3	c.497C>T	p.Ala166Val	missense_variant	Exon 8 of 20	ENST00000331366.10	NP_705898.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPNE8	ENST00000331366.10	c.497C>T	p.Ala166Val	missense_variant	Exon 8 of 20	1	NM_153634.3	ENSP00000329748.5
CPNE8	ENST00000360449.3	c.461C>T	p.Ala154Val	missense_variant	Exon 8 of 20	2		ENSP00000353633.3
CPNE8	ENST00000550863.1	c.14C>T	p.Ala5Val	missense_variant	Exon 8 of 8	4		ENSP00000447761.1
CPNE8	ENST00000551855.1	n.5C>T		non_coding_transcript_exon_variant	Exon 1 of 5	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000573 AC: 8 AN: 1395768 Hom.: 0 Cov.: 29 AF XY: 0.00000579 AC XY: 4 AN XY: 691424

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000300

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000138

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000461

Gnomad4 OTH exome AF: 0.0000173

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.497C>T (p.A166V) alteration is located in exon 8 (coding exon 8) of the CPNE8 gene. This alteration results from a C to T substitution at nucleotide position 497, causing the alanine (A) at amino acid position 166 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.061	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T;.;.
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.99	D;D;.
M_CAP	Benign	0.083	D
MetaRNN	Pathogenic	0.85	D;D;D
MetaSVM	Uncertain	-0.025	T
MutationAssessor	Pathogenic	3.8	H;.;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.2	D;D;D
REVEL	Uncertain	0.40
Sift	Uncertain	0.018	D;D;.
Sift4G	Uncertain	0.022	D;D;.
Polyphen		0.12	B;.;.
Vest4		0.76
MutPred		0.82		Loss of catalytic residue at A166 (P = 0.0574);.;.;
MVP		0.75
MPC		0.36
ClinPred		0.99	D
GERP RS		4.2
Varity_R		0.41
gMVP		0.61

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

Publications

LitVar

Other links and lift over

dbSNP: rs750050507; hg19: chr12-39161515; COSMIC: COSV58844155;