Genetic Variant CCM2:p.Met1? (chr7-45000336-G-A) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PS1_ModeratePM2

The NM_031443.4(CCM2):c.3G>A(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 25)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CCM2
NM_031443.4 start_lost

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.37

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: Pathogenic. The variant received 12 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 78 pathogenic variants. Next in-frame start position is after 303 codons. Genomic position: 45073563. Lost 0.679 part of the original CDS.

PS1

Another start lost variant in NM_031443.4 (CCM2) was described as [Pathogenic] in ClinVar

PM2

Very rare variant in population databases, with high coverage;

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	HGVSp	Effect	Exon Rank	Protein	UniProt
CCM2	NM_031443.4	MANE Select	c.3G>A	p.Met1?	start_lost	Exon 1 of 10	NP_113631.1	Q9BSQ5-1
CCM2	NM_001363458.2		c.3G>A	p.Met1?	start_lost	Exon 1 of 11	NP_001350387.1
CCM2	NM_001363459.2		c.3G>A	p.Met1?	start_lost	Exon 1 of 10	NP_001350388.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CCM2	ENST00000258781.11	TSL:1 MANE Select	c.3G>A	p.Met1?	start_lost	Exon 1 of 10	ENSP00000258781.7	Q9BSQ5-1
CCM2	ENST00000938553.1		c.3G>A	p.Met1?	start_lost	Exon 1 of 11	ENSP00000608612.1
CCM2	ENST00000956241.1		c.3G>A	p.Met1?	start_lost	Exon 1 of 12	ENSP00000626300.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1145190

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

552686

African (AFR)

AF:

0.00

AC:

AN:

23770

American (AMR)

AF:

0.00

AC:

AN:

14058

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17040

East Asian (EAS)

AF:

0.00

AC:

AN:

26816

South Asian (SAS)

AF:

0.00

AC:

AN:

30076

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37236

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3142

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

947340

Other (OTH)

AF:

0.00

AC:

AN:

45712

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.62

BayesDel_noAF

Uncertain

-0.020

CADD

Uncertain

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.25

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.0035

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.70

MetaRNN

Uncertain

0.52

MetaSVM

Benign

-0.93

PhyloP100

2.4

PROVEAN

Uncertain

-2.5

REVEL

Benign

0.23

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.0050

Vest4

0.66

MutPred

0.55

Gain of catalytic residue at M1 (P = 0.1331)

MVP

0.49

ClinPred

0.82

GERP RS

2.0

PromoterAI

-0.11

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.85

Mutation Taster

=15/185

disease causing

(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

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