Variant 16-57115549-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_152727.6(CPNE2):c.434C>T(p.Thr145Met) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000807 in 1,609,918 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

CPNE2
NM_152727.6 missense, splice_region

Scores

Splicing: ADA: 0.02215

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.71

Variant links:

Genes affected

CPNE2 (HGNC:2315): (copine 2) 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. Sequence analysis identified multiple alternatively spliced transcript variants but their full-length natures could not be determined. [provided by RefSeq, Jul 2008]

CPNE2 links:

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ACMG classification

Classification made for transcript

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=0.25865066).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CPNE2	NM_152727.6 linkuse as main transcript	c.434C>T	p.Thr145Met	missense_variant, splice_region_variant	4/16	ENST00000290776.13	NP_689940.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CPNE2	ENST00000290776.13 linkuse as main transcript	c.434C>T	p.Thr145Met	missense_variant, splice_region_variant	4/16	1	NM_152727.6	ENSP00000290776	P1	Q96FN4-1
CPNE2	ENST00000535318.6 linkuse as main transcript	c.434C>T	p.Thr145Met	missense_variant, splice_region_variant	5/17	1		ENSP00000439018	P1	Q96FN4-1
CPNE2	ENST00000565874.5 linkuse as main transcript	c.434C>T	p.Thr145Met	missense_variant, splice_region_variant	3/15	1		ENSP00000456042	P1	Q96FN4-1
CPNE2	ENST00000567487.1 linkuse as main transcript	c.128C>T	p.Thr43Met	missense_variant, splice_region_variant	2/5	2		ENSP00000455443

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000242

AC:

AN:

247608

Hom.:

AF XY:

0.0000149

AC XY:

AN XY:

134028

show subpopulations

Gnomad AFR exome

AF:

0.000312

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000331

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000412

AC:

AN:

1457696

Hom.:

Cov.:

AF XY:

0.00000689

AC XY:

AN XY:

725222

show subpopulations

Gnomad4 AFR exome

AF:

0.000150

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000869

ESP6500AA

AF:

0.000455

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 30, 2024

The c.434C>T (p.T145M) alteration is located in exon 4 (coding exon 3) of the CPNE2 gene. This alteration results from a C to T substitution at nucleotide position 434, causing the threonine (T) at amino acid position 145 to be replaced by a methionine (M). 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

-0.29

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.28

T;T;T;.

Eigen

Uncertain

0.22

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.79

.;.;T;T

M_CAP

Benign

0.046

MetaRNN

Benign

0.26

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.8

M;M;M;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-4.9

D;D;D;D

REVEL

Benign

0.16

Sift

Uncertain

0.021

D;D;D;D

Sift4G

Uncertain

0.019

D;D;D;T

Polyphen

0.67

P;P;P;.

Vest4

0.45

MVP

0.27

MPC

0.52

ClinPred

0.61

GERP RS

3.8

Varity_R

0.57

gMVP

0.62

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.022

dbscSNV1_RF

Benign

0.37

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over