Genetic Variant NM_020939.2:c.1564-6T>C (chr6-36742492-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_020939.2(CPNE5):c.1564-6T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.194 in 1,607,348 control chromosomes in the GnomAD database, including 31,702 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 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: 𝑓 0.17 ( 2395 hom., cov: 32)

Exomes 𝑓: 0.20 ( 29307 hom. )

Consequence

CPNE5
NM_020939.2 splice_region, intron

Scores

Splicing: ADA: 0.0003679

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.13

Publications

14 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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.255 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPNE5	NM_020939.2 link	c.1564-6T>C		splice_region_variant, intron_variant	Intron 20 of 20	ENST00000244751.7	NP_065990.1	Q9HCH3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPNE5	ENST00000244751.7 link	c.1564-6T>C		splice_region_variant, intron_variant	Intron 20 of 20	1	NM_020939.2	ENSP00000244751.2		Q9HCH3-1

Frequencies

GnomAD3 genomes

AF:

0.166

AC:

25211

AN:

151938

Hom.:

2398

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0643

Gnomad AMI

AF:

0.187

Gnomad AMR

AF:

0.201

Gnomad ASJ

AF:

0.188

Gnomad EAS

AF:

0.268

Gnomad SAS

AF:

0.213

Gnomad FIN

AF:

0.176

Gnomad MID

AF:

0.168

Gnomad NFE

AF:

0.206

Gnomad OTH

AF:

0.171

GnomAD2 exomes

AF:

0.195

AC:

48092

AN:

246112

AF XY:

0.198

show subpopulations

Gnomad AFR exome

AF:

0.0637

Gnomad AMR exome

AF:

0.194

Gnomad ASJ exome

AF:

0.179

Gnomad EAS exome

AF:

0.273

Gnomad FIN exome

AF:

0.177

Gnomad NFE exome

AF:

0.201

Gnomad OTH exome

AF:

0.211

GnomAD4 exome

AF:

0.197

AC:

286647

AN:

1455292

Hom.:

29307

Cov.:

AF XY:

0.198

AC XY:

143503

AN XY:

723504

show subpopulations

African (AFR)

AF:

0.0597

AC:

1994

AN:

33414

American (AMR)

AF:

0.195

AC:

8723

AN:

44630

Ashkenazi Jewish (ASJ)

AF:

0.181

AC:

4725

AN:

26064

East Asian (EAS)

AF:

0.284

AC:

11249

AN:

39600

South Asian (SAS)

AF:

0.213

AC:

18345

AN:

86182

European-Finnish (FIN)

AF:

0.173

AC:

8651

AN:

49942

Middle Eastern (MID)

AF:

0.179

AC:

1029

AN:

5756

European-Non Finnish (NFE)

AF:

0.199

AC:

220296

AN:

1109516

Other (OTH)

AF:

0.193

AC:

11635

AN:

60188

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

13278

26556

39834

53112

66390

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7568

15136

22704

30272

37840

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.166

AC:

25195

AN:

152056

Hom.:

2395

Cov.:

AF XY:

0.167

AC XY:

12425

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.0641

AC:

2662

AN:

41498

American (AMR)

AF:

0.201

AC:

3072

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.188

AC:

653

AN:

3468

East Asian (EAS)

AF:

0.267

AC:

1374

AN:

5152

South Asian (SAS)

AF:

0.212

AC:

1025

AN:

4828

European-Finnish (FIN)

AF:

0.176

AC:

1864

AN:

10584

Middle Eastern (MID)

AF:

0.173

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.206

AC:

13965

AN:

67930

Other (OTH)

AF:

0.170

AC:

359

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1063

2126

3190

4253

5316

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

284

568

852

1136

1420

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.191

Hom.:

9915

Bravo

AF:

0.162

Asia WGS

AF:

0.194

AC:

676

AN:

3478

EpiCase

AF:

0.211

EpiControl

AF:

0.211

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

3.3

(source)

DANN

Benign

0.51

PhyloP100

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00037

dbscSNV1_RF

Benign

0.040

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over