Genetic Variant CCM2:c.30+101G>A (chr7-45000464-G-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_031443.4(CCM2):c.30+101G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. 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 0.0000096 ( 0 hom., cov: 14)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CCM2
NM_031443.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.32

Publications

2 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: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

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+101G>A	intron	N/A	NP_113631.1	Q9BSQ5-1
CCM2	NM_001363458.2		c.30+101G>A	intron	N/A	NP_001350387.1
CCM2	NM_001363459.2		c.30+101G>A	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+101G>A	intron	N/A	ENSP00000258781.7	Q9BSQ5-1
CCM2	ENST00000938553.1		c.30+101G>A	intron	N/A	ENSP00000608612.1
CCM2	ENST00000956241.1		c.30+101G>A	intron	N/A	ENSP00000626300.1

Frequencies

GnomAD3 genomes

AF:

0.00000964

AC:

AN:

103692

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:

0.0000199

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

86722

Hom.:

AF XY:

0.00

AC XY:

AN XY:

44148

African (AFR)

AF:

0.00

AC:

AN:

1760

American (AMR)

AF:

0.00

AC:

AN:

2196

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3200

East Asian (EAS)

AF:

0.00

AC:

AN:

9842

South Asian (SAS)

AF:

0.00

AC:

AN:

686

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8306

Middle Eastern (MID)

AF:

0.00

AC:

AN:

434

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

54852

Other (OTH)

AF:

0.00

AC:

AN:

5446

GnomAD4 genome

AF:

0.00000964

AC:

AN:

103692

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

48922

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26636

American (AMR)

AF:

0.00

AC:

AN:

10304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2702

East Asian (EAS)

AF:

0.00

AC:

AN:

3352

South Asian (SAS)

AF:

0.00

AC:

AN:

2756

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5566

Middle Eastern (MID)

AF:

0.00

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.0000199

AC:

AN:

50142

Other (OTH)

AF:

0.00

AC:

AN:

1396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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

BayesDel_noAF

Benign

-0.79

CADD

Benign

7.9

(source)

DANN

Benign

0.96

PhyloP100

-2.3

PromoterAI

0.017

Neutral

(source)

RBP_binding_hub_radar

0.77

RBP_regulation_power_radar

3.3

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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