12-38762209-T-A

Variant names:

• chr12-38762209-T-A
• rs769858371
• NM_153634.3:c.583A>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_153634.3(CPNE8):​c.583A>T​(p.Ile195Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000211 in 1,418,546 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I195V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CPNE8 NM_153634.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.01
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.815

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.583A>T	p.Ile195Phe	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.583A>T	p.Ile195Phe	missense	Exon 9 of 20	ENSP00000329748.5	Q86YQ8-1
	CPNE8	ENST00000360449.3	TSL:2	c.547A>T	p.Ile183Phe	missense	Exon 9 of 20	ENSP00000353633.3	E7ENV7
	CPNE8	ENST00000862791.1		c.583A>T	p.Ile195Phe	missense	Exon 9 of 20	ENSP00000532850.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000211 AC: 3 AN: 1418546 Hom.: 0 Cov.: 23 AF XY: 0.00000283 AC XY: 2 AN XY: 706932

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31798

American (AMR) AF: 0.00 AC: 0 AN: 39772

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25238

East Asian (EAS) AF: 0.00 AC: 0 AN: 39032

South Asian (SAS) AF: 0.00 AC: 0 AN: 81228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52660

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5628

European-Non Finnish (NFE) AF: 0.00000277 AC: 3 AN: 1084450

Other (OTH) AF: 0.00 AC: 0 AN: 58740

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0136242), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Benign	0.072	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	0.66	N
PhyloP100		6.0
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.012	D
Polyphen		0.98	D
Vest4		0.88
MutPred		0.48		Gain of ubiquitination at K198 (P = 0.0837)
MVP		0.69
MPC		1.5
ClinPred		0.98	D
GERP RS		3.9
Varity_R		0.55
gMVP		0.46
Mutation Taster		=33/67	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: rs769858371; hg19: chr12-39156011;