14-24073600-C-A

Variant names:

• chr14-24073600-C-A
• NM_006032.4:c.270C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006032.4(CPNE6):​c.270C>A​(p.His90Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CPNE6 NM_006032.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -3.67

Genes affected

CPNE6 (HGNC:2319): (copine 6) This gene encodes a member of the copine family. Members of this family are calcium-dependent, phospholipid-binding proteins with C2 domains, two calcium- and phospholipid-binding domains. Through their domain structure and lipid binding capabilities, these proteins may play a role in membrane trafficking. This protein is thought to be brain-specific and has a domain structure of two N-terminal C2 domains and one von Willebrand factor A domain. It may have a role in synaptic plasticity. [provided by RefSeq, Jul 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1473284).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPNE6	NM_006032.4	c.270C>A	p.His90Gln	missense_variant	Exon 3 of 17	ENST00000689861.1	NP_006023.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPNE6	ENST00000689861.1	c.270C>A	p.His90Gln	missense_variant	Exon 3 of 17		NM_006032.4	ENSP00000510387.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461724 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727144

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.270C>A (p.H90Q) alteration is located in exon 3 (coding exon 2) of the CPNE6 gene. This alteration results from a C to A substitution at nucleotide position 270, causing the histidine (H) at amino acid position 90 to be replaced by a glutamine (Q). 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	Benign	0.12
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	0.56
DANN	Benign	0.89
DEOGEN2	Benign	0.083	.;T;T;T;T;.;.;T;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.054	N
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.15	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.17	.;N;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	0.33	N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.15
Sift	Benign	0.30	T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.32	T;T;T;T;T;T;T;T;T;T
Polyphen		0.31	.;B;.;.;.;.;.;.;.;.
Vest4		0.50
MutPred		0.52		.;Gain of catalytic residue at F92 (P = 0.0091);Gain of catalytic residue at F92 (P = 0.0091);Gain of catalytic residue at F92 (P = 0.0091);Gain of catalytic residue at F92 (P = 0.0091);Gain of catalytic residue at F92 (P = 0.0091);Gain of catalytic residue at F92 (P = 0.0091);.;Gain of catalytic residue at F92 (P = 0.0091);Gain of catalytic residue at F92 (P = 0.0091);
MVP		0.72
MPC		0.64
ClinPred		0.43	T
GERP RS		-4.0
Varity_R		0.049
gMVP		0.29

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-24542809;