Genetic Variant CCM2:c.30+94_30+95insA (chr7-45000457-G-GA) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

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

The NM_031443.4(CCM2):c.30+94_30+95insA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000178 in 337,320 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000025 ( 0 hom., cov: 19)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

CCM2
NM_031443.4 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.188

Publications

0 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), ClinGen, Genomics England PanelApp
famililal cerebral cavernous malformations
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CCM2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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.30+94_30+95insA	intron	N/A	NP_113631.1	Q9BSQ5-1
CCM2	NM_001363458.2		c.30+94_30+95insA	intron	N/A	NP_001350387.1
CCM2	NM_001363459.2		c.30+94_30+95insA	intron	N/A	NP_001350388.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CCM2	ENST00000258781.11	TSL:1 MANE Select	c.30+94_30+95insA	intron	N/A	ENSP00000258781.7	Q9BSQ5-1
CCM2	ENST00000938553.1		c.30+94_30+95insA	intron	N/A	ENSP00000608612.1
CCM2	ENST00000956241.1		c.30+94_30+95insA	intron	N/A	ENSP00000626300.1

Frequencies

GnomAD3 genomes

AF:

0.0000246

AC:

AN:

122022

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000544

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000139

AC:

AN:

215298

Hom.:

AF XY:

0.00000922

AC XY:

AN XY:

108418

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

4322

American (AMR)

AF:

0.00

AC:

AN:

4738

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

6292

East Asian (EAS)

AF:

0.00

AC:

AN:

18184

South Asian (SAS)

AF:

0.00

AC:

AN:

2500

European-Finnish (FIN)

AF:

0.00

AC:

AN:

14392

Middle Eastern (MID)

AF:

0.00

AC:

AN:

950

European-Non Finnish (NFE)

AF:

0.0000132

AC:

AN:

151718

Other (OTH)

AF:

0.0000820

AC:

AN:

12202

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.608

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000246

AC:

AN:

122022

Hom.:

Cov.:

AF XY:

0.0000170

AC XY:

AN XY:

58850

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32876

American (AMR)

AF:

0.00

AC:

AN:

12960

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2950

East Asian (EAS)

AF:

0.00

AC:

AN:

3742

South Asian (SAS)

AF:

0.00

AC:

AN:

3460

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8368

Middle Eastern (MID)

AF:

0.00

AC:

AN:

272

European-Non Finnish (NFE)

AF:

0.0000544

AC:

AN:

55126

Other (OTH)

AF:

0.00

AC:

AN:

1586

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.19

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over