rs2289366

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001363458.2(CCM2):c.989G>A(p.Ser330Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00438 in 1,613,166 control chromosomes in the GnomAD database, including 437 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S330S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0075 ( 55 hom., cov: 33)

Exomes 𝑓: 0.0041 ( 382 hom. )

Consequence

CCM2
NM_001363458.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 7.69

Publications

8 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0018657148).

BP6

Variant 7-45073522-G-A is Benign according to our data. Variant chr7-45073522-G-A is described in ClinVar as Benign. ClinVar VariationId is 261974.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.059 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001363458.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CCM2	NM_031443.4	MANE Select	c.866G>A	p.Ser289Asn	missense	Exon 8 of 10	NP_113631.1
CCM2	NM_001363458.2		c.989G>A	p.Ser330Asn	missense	Exon 9 of 11	NP_001350387.1
CCM2	NM_001029835.2		c.929G>A	p.Ser310Asn	missense	Exon 8 of 10	NP_001025006.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CCM2	ENST00000258781.11	TSL:1 MANE Select	c.866G>A	p.Ser289Asn	missense	Exon 8 of 10	ENSP00000258781.7
CCM2	ENST00000477605.1	TSL:1	n.1201G>A		non_coding_transcript_exon	Exon 4 of 6
CCM2	ENST00000481194.1	TSL:1	n.3741G>A		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes

AF:

0.00738

AC:

1123

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00239

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0615

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00712

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00669

GnomAD2 exomes

AF:

0.0173

AC:

4320

AN:

250050

AF XY:

0.0135

show subpopulations

Gnomad AFR exome

AF:

0.00235

Gnomad AMR exome

AF:

0.116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00680

Gnomad FIN exome

AF:

0.000562

Gnomad NFE exome

AF:

0.000195

Gnomad OTH exome

AF:

0.00951

GnomAD4 exome

AF:

0.00405

AC:

5922

AN:

1460828

Hom.:

382

Cov.:

AF XY:

0.00359

AC XY:

2607

AN XY:

726716

show subpopulations

African (AFR)

AF:

0.00116

AC:

AN:

33480

American (AMR)

AF:

0.111

AC:

4951

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00829

AC:

329

AN:

39700

South Asian (SAS)

AF:

0.00228

AC:

197

AN:

86254

European-Finnish (FIN)

AF:

0.000400

AC:

AN:

52486

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000141

AC:

157

AN:

1111936

Other (OTH)

AF:

0.00374

AC:

226

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

292

585

877

1170

1462

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

168

252

336

420

<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:

0.00746

AC:

1136

AN:

152338

Hom.:

Cov.:

AF XY:

0.00800

AC XY:

596

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.00238

AC:

AN:

41586

American (AMR)

AF:

0.0623

AC:

953

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00714

AC:

AN:

5184

South Asian (SAS)

AF:

0.00290

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000565

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000191

AC:

AN:

68040

Other (OTH)

AF:

0.00662

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

104

155

207

259

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00581

Hom.:

103

Bravo

AF:

0.0130

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.0130

AC:

1574

Asia WGS

AF:

0.00866

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000296

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

Cerebral cavernous malformation 2 (2)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.41

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

MetaRNN

Benign

0.0019

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.5

PhyloP100

7.7

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-1.8

REVEL

Benign

0.17

Sift

Benign

0.074

Sift4G

Uncertain

0.051

Polyphen

0.87

Vest4

0.20

MPC

0.68

ClinPred

0.026

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.47

gMVP

0.42

Mutation Taster

=75/25

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over