Genetic Variant NM_031443.4:c.351G>A (chr7-45064525-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_031443.4(CCM2):c.351G>A(p.Ala117Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00724 in 1,613,824 control chromosomes in the GnomAD database, including 737 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.038 ( 379 hom., cov: 32)

Exomes 𝑓: 0.0040 ( 358 hom. )

Consequence

CCM2
NM_031443.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.292

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.5).

BP6

Variant 7-45064525-G-A is Benign according to our data. Variant chr7-45064525-G-A is described in ClinVar as Benign. ClinVar VariationId is 261970.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.292 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.129 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	HGVSp	Effect	Exon Rank	Protein
CCM2	NM_031443.4	MANE Select	c.351G>A	p.Ala117Ala	synonymous	Exon 4 of 10	NP_113631.1
CCM2	NM_001363458.2		c.351G>A	p.Ala117Ala	synonymous	Exon 4 of 11	NP_001350387.1
CCM2	NM_001029835.2		c.414G>A	p.Ala138Ala	synonymous	Exon 4 of 10	NP_001025006.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CCM2	ENST00000258781.11	TSL:1 MANE Select	c.351G>A	p.Ala117Ala	synonymous	Exon 4 of 10	ENSP00000258781.7
CCM2	ENST00000381112.7	TSL:2	c.414G>A	p.Ala138Ala	synonymous	Exon 4 of 10	ENSP00000370503.3
CCM2	ENST00000475551.5	TSL:2	c.333G>A	p.Ala111Ala	synonymous	Exon 4 of 10	ENSP00000417180.1

Frequencies

GnomAD3 genomes

AF:

0.0379

AC:

5770

AN:

152140

Hom.:

374

Cov.:

show subpopulations

Gnomad AFR

AF:

0.131

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0155

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000544

Gnomad OTH

AF:

0.0263

GnomAD2 exomes

AF:

0.0101

AC:

2534

AN:

251088

AF XY:

0.00760

show subpopulations

Gnomad AFR exome

AF:

0.135

Gnomad AMR exome

AF:

0.00767

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000405

Gnomad OTH exome

AF:

0.00392

GnomAD4 exome

AF:

0.00402

AC:

5875

AN:

1461568

Hom.:

358

Cov.:

AF XY:

0.00350

AC XY:

2542

AN XY:

727082

show subpopulations

African (AFR)

AF:

0.137

AC:

4582

AN:

33470

American (AMR)

AF:

0.00890

AC:

398

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.000360

AC:

AN:

86216

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53390

Middle Eastern (MID)

AF:

0.00371

AC:

AN:

5666

European-Non Finnish (NFE)

AF:

0.000237

AC:

264

AN:

1111924

Other (OTH)

AF:

0.00959

AC:

579

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

322

644

967

1289

1611

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

138

276

414

552

690

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0381

AC:

5802

AN:

152256

Hom.:

379

Cov.:

AF XY:

0.0364

AC XY:

2712

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.132

AC:

5464

AN:

41504

American (AMR)

AF:

0.0155

AC:

237

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00104

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000544

AC:

AN:

68040

Other (OTH)

AF:

0.0260

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

252

505

757

1010

1262

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

168

224

280

<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:

0.0162

Hom.:

Bravo

AF:

0.0438

Asia WGS

AF:

0.00808

AC:

AN:

3478

EpiCase

AF:

0.000545

EpiControl

AF:

0.000593

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Jan 16, 2018

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 14, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Cerebral cavernous malformation 2

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.71

PhyloP100

0.29

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=89/11

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

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over