Genetic Variant NM_020939.2:c.98A>C (chr6-36823096-T-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_020939.2(CPNE5):c.98A>C(p.Asn33Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000707 in 1,414,870 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

CPNE5
NM_020939.2 missense, splice_region

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.22

Publications

0 publications found

Variant links:

Genes affected

CPNE5 (HGNC:2318): (copine 5) 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. Several alternatively spliced transcript variants encoding different isoforms have been found for this gene. More variants may exist, but their full-length natures could not be determined. [provided by RefSeq, Sep 2015]

CPNE5 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPNE5	NM_020939.2 link	c.98A>C	p.Asn33Thr	missense_variant, splice_region_variant	Exon 2 of 21	ENST00000244751.7	NP_065990.1	Q9HCH3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CPNE5	ENST00000244751.7 link	c.98A>C	p.Asn33Thr	missense_variant, splice_region_variant	Exon 2 of 21	1	NM_020939.2	ENSP00000244751.2	Q9HCH3-1
CPNE5	ENST00000633136.2 link	c.98A>C	p.Asn33Thr	missense_variant, splice_region_variant	Exon 2 of 22	5		ENSP00000487872.2	A0A0J9YWA1
CPNE5	ENST00000633280.1 link	c.98A>C	p.Asn33Thr	missense_variant, splice_region_variant	Exon 2 of 10	5		ENSP00000488125.1	A0A0J9YWU8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.07e-7

AC:

AN:

1414870

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

701674

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

32324

American (AMR)

AF:

0.0000248

AC:

AN:

40290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25380

East Asian (EAS)

AF:

0.00

AC:

AN:

36906

South Asian (SAS)

AF:

0.00

AC:

AN:

77160

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52758

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5064

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1086554

Other (OTH)

AF:

0.00

AC:

AN:

58434

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Benign

0.0083

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.48

T;T;T

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.63

T;T;T

M_CAP

Benign

0.072

MetaRNN

Uncertain

0.55

D;D;D

MetaSVM

Benign

-0.41

MutationAssessor

Pathogenic

3.7

H;.;.

PhyloP100

2.2

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-3.8

D;.;.

REVEL

Uncertain

0.36

Sift

Uncertain

0.0060

D;.;.

Sift4G

Uncertain

0.015

D;D;D

Polyphen

0.96

D;.;.

Vest4

0.54

MutPred

0.51

Loss of stability (P = 0.0156);.;Loss of stability (P = 0.0156);

MVP

0.73

MPC

1.5

ClinPred

0.99

GERP RS

4.3

Varity_R

0.37

gMVP

0.40

Mutation Taster

=54/46

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over