Genetic Variant CCM2:p.Val190Leu (chr7-45068538-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_031443.4(CCM2):c.568G>T(p.Val190Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V190M) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CCM2
NM_031443.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.80

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), 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 2 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_031443.4

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.20897064).

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
CCM2	NM_031443.4	MANE Select	c.568G>T	p.Val190Leu	missense	Exon 5 of 10	NP_113631.1
CCM2	NM_001363458.2		c.568G>T	p.Val190Leu	missense	Exon 5 of 11	NP_001350387.1
CCM2	NM_001029835.2		c.631G>T	p.Val211Leu	missense	Exon 5 of 10	NP_001025006.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CCM2	ENST00000258781.11	TSL:1 MANE Select	c.568G>T	p.Val190Leu	missense	Exon 5 of 10	ENSP00000258781.7
CCM2	ENST00000477605.1	TSL:1	n.903G>T		non_coding_transcript_exon	Exon 1 of 6
CCM2	ENST00000481194.1	TSL:1	n.45-1288G>T		intron	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461834

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727224

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53368

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112006

Other (OTH)

AF:

0.00

AC:

AN:

60394

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

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

0.00071

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.10

Eigen

Benign

0.023

Eigen_PC

Benign

0.063

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.016

MetaRNN

Benign

0.21

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.3

PhyloP100

4.8

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.060

REVEL

Benign

0.14

Sift

Benign

0.70

Sift4G

Benign

0.53

Polyphen

0.76

Vest4

0.35

MutPred

0.15

Gain of stability (P = 0.0614)

MVP

0.36

MPC

0.32

ClinPred

0.79

GERP RS

3.9

PromoterAI

0.052

Neutral

(source)

Varity_R

0.11

gMVP

0.43

Mutation Taster

=39/61

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

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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