rs2289367

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PP3_ModerateBP6_Very_StrongBA1

The NM_031443.4(CCM2):c.915G>A(p.Thr305Thr) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.218 in 1,602,280 control chromosomes in the GnomAD database, including 39,162 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.22 ( 3852 hom., cov: 32)

Exomes 𝑓: 0.22 ( 35310 hom. )

Consequence

CCM2
NM_031443.4 splice_region, synonymous

Scores

Splicing: ADA: 0.9997

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.17

Publications

38 publications found

Variant links:

Genes affected

CCM2 (HGNC:21708): (CCM2 scaffold protein) This gene encodes a scaffold protein that functions in the stress-activated p38 Mitogen-activated protein kinase (MAPK) signaling cascade. The protein interacts with SMAD specific E3 ubiquitin protein ligase 1 (also known as SMURF1) via a phosphotyrosine binding domain to promote RhoA degradation. The protein is required for normal cytoskeletal structure, cell-cell interactions, and lumen formation in endothelial cells. Mutations in this gene result in cerebral cavernous malformations. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Nov 2009]

CCM2 Gene-Disease associations (from GenCC):

cerebral cavernous malformation 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
famililal cerebral cavernous malformations
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CCM2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

BP6

Variant 7-45073571-G-A is Benign according to our data. Variant chr7-45073571-G-A is described in ClinVar as Benign. ClinVar VariationId is 261975.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.251 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCM2	NM_031443.4 link	c.915G>A	p.Thr305Thr	splice_region_variant, synonymous_variant	Exon 8 of 10	ENST00000258781.11	NP_113631.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCM2	ENST00000258781.11 link	c.915G>A	p.Thr305Thr	splice_region_variant, synonymous_variant	Exon 8 of 10	1	NM_031443.4	ENSP00000258781.7

Frequencies

GnomAD3 genomes

AF:

0.225

AC:

34144

AN:

152004

Hom.:

3847

Cov.:

show subpopulations

Gnomad AFR

AF:

0.254

Gnomad AMI

AF:

0.168

Gnomad AMR

AF:

0.256

Gnomad ASJ

AF:

0.181

Gnomad EAS

AF:

0.192

Gnomad SAS

AF:

0.212

Gnomad FIN

AF:

0.206

Gnomad MID

AF:

0.136

Gnomad NFE

AF:

0.210

Gnomad OTH

AF:

0.191

GnomAD2 exomes

AF:

0.231

AC:

56546

AN:

245312

AF XY:

0.223

show subpopulations

Gnomad AFR exome

AF:

0.249

Gnomad AMR exome

AF:

0.358

Gnomad ASJ exome

AF:

0.181

Gnomad EAS exome

AF:

0.197

Gnomad FIN exome

AF:

0.208

Gnomad NFE exome

AF:

0.207

Gnomad OTH exome

AF:

0.208

GnomAD4 exome

AF:

0.217

AC:

315144

AN:

1450158

Hom.:

35310

Cov.:

AF XY:

0.216

AC XY:

155638

AN XY:

721236

show subpopulations

African (AFR)

AF:

0.255

AC:

8512

AN:

33344

American (AMR)

AF:

0.344

AC:

15299

AN:

44424

Ashkenazi Jewish (ASJ)

AF:

0.180

AC:

4684

AN:

26056

East Asian (EAS)

AF:

0.178

AC:

7024

AN:

39564

South Asian (SAS)

AF:

0.216

AC:

18582

AN:

86046

European-Finnish (FIN)

AF:

0.205

AC:

10319

AN:

50308

Middle Eastern (MID)

AF:

0.182

AC:

1034

AN:

5674

European-Non Finnish (NFE)

AF:

0.215

AC:

237223

AN:

1104704

Other (OTH)

AF:

0.208

AC:

12467

AN:

60038

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

11651

23302

34953

46604

58255

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8416

16832

25248

33664

42080

<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:

0.225

AC:

34179

AN:

152122

Hom.:

3852

Cov.:

AF XY:

0.224

AC XY:

16675

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.255

AC:

10566

AN:

41484

American (AMR)

AF:

0.256

AC:

3914

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.181

AC:

630

AN:

3472

East Asian (EAS)

AF:

0.192

AC:

991

AN:

5162

South Asian (SAS)

AF:

0.212

AC:

1025

AN:

4828

European-Finnish (FIN)

AF:

0.206

AC:

2179

AN:

10600

Middle Eastern (MID)

AF:

0.136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.210

AC:

14282

AN:

67978

Other (OTH)

AF:

0.189

AC:

399

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1353

2707

4060

5414

6767

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

354

708

1062

1416

1770

<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:

0.213

Hom.:

13943

Bravo

AF:

0.233

Asia WGS

AF:

0.197

AC:

688

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cerebral cavernous malformation 2

Benign:4

Oct 10, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 23, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Nov 24, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 27708576) -

CCM2-related disorder

Benign:1

Jul 02, 2024

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not specified

Benign:1

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Benign

0.77

PhyloP100

1.2

Mutation Taster

=20/80

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over