dbSNP rs10280402: CCM2:c.204+10993C>T (chr7-45049419-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_031443.4(CCM2):c.204+10993C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.133 in 152,224 control chromosomes in the GnomAD database, including 1,661 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.13 ( 1661 hom., cov: 32)

Consequence

CCM2
NM_031443.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0620

Publications

3 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: Genomics England PanelApp, ClinGen, G2P, Labcorp Genetics (formerly Invitae)
famililal cerebral cavernous malformations
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CCM2 links:

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new If you want to explore the variant's impact on the transcript NM_031443.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

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=-0.95).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.178 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031443.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CCM2	NM_031443.4	MANE Select	c.204+10993C>T	intron	N/A	NP_113631.1	Q9BSQ5-1
CCM2	NM_001363458.2		c.204+10993C>T	intron	N/A	NP_001350387.1
CCM2	NM_001029835.2		c.267+10993C>T	intron	N/A	NP_001025006.1	Q9BSQ5-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CCM2	ENST00000258781.11	TSL:1 MANE Select	c.204+10993C>T	intron	N/A	ENSP00000258781.7	Q9BSQ5-1
CCM2	ENST00000938553.1		c.369+10993C>T	intron	N/A	ENSP00000608612.1
CCM2	ENST00000956241.1		c.204+10993C>T	intron	N/A	ENSP00000626300.1

Frequencies

GnomAD3 genomes

AF:

0.133

AC:

20299

AN:

152106

Hom.:

1663

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0389

Gnomad AMI

AF:

0.0998

Gnomad AMR

AF:

0.173

Gnomad ASJ

AF:

0.224

Gnomad EAS

AF:

0.0904

Gnomad SAS

AF:

0.143

Gnomad FIN

AF:

0.122

Gnomad MID

AF:

0.231

Gnomad NFE

AF:

0.181

Gnomad OTH

AF:

0.177

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.133

AC:

20299

AN:

152224

Hom.:

1661

Cov.:

AF XY:

0.131

AC XY:

9737

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.0388

AC:

1613

AN:

41548

American (AMR)

AF:

0.173

AC:

2646

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.224

AC:

777

AN:

3470

East Asian (EAS)

AF:

0.0902

AC:

468

AN:

5186

South Asian (SAS)

AF:

0.143

AC:

692

AN:

4828

European-Finnish (FIN)

AF:

0.122

AC:

1290

AN:

10590

Middle Eastern (MID)

AF:

0.228

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.181

AC:

12282

AN:

68002

Other (OTH)

AF:

0.177

AC:

373

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

894

1789

2683

3578

4472

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

230

460

690

920

1150

<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:

0.155

Hom.:

262

Bravo

AF:

0.129

Asia WGS

AF:

0.138

AC:

480

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.95

CADD

Benign

5.9

(source)

DANN

Benign

0.82

PhyloP100

0.062

Mutation Taster

=100/0

polymorphism (auto)

(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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over