Genetic Variant CCM2:n.383+304_383+305insTGCCTGCTCT (chr7-45000161-G-GTGCCTGCTCT) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

The NR_030770.2(CCM2):n.112+304_112+305insTGCCTGCTCT variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00052 ( 3 hom., cov: 0)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CCM2
NR_030770.2 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.25

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:

ENSG00000309655 (HGNC:):

ENSG00000309655 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000521 (59/113346) while in subpopulation AFR AF = 0.00184 (52/28288). AF 95% confidence interval is 0.00144. There are 3 homozygotes in GnomAd4. There are 24 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High AC in GnomAd4 at 59 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NR_030770.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CCM2	NR_030770.2		n.112+304_112+305insTGCCTGCTCT	intron	N/A
CCM2	NM_031443.4	MANE Select	c.-173_-172insTGCCTGCTCT	upstream_gene	N/A	NP_113631.1	Q9BSQ5-1
CCM2	NM_001363458.2		c.-173_-172insTGCCTGCTCT	upstream_gene	N/A	NP_001350387.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CCM2	ENST00000461377.5	TSL:5	n.383+304_383+305insTGCCTGCTCT	intron	N/A
CCM2	ENST00000258781.11	TSL:1 MANE Select	c.-173_-172insTGCCTGCTCT	upstream_gene	N/A	ENSP00000258781.7	Q9BSQ5-1
CCM2	ENST00000938553.1		c.-173_-172insTGCCTGCTCT	upstream_gene	N/A	ENSP00000608612.1

Frequencies

GnomAD3 genomes

AF:

0.000521

AC:

AN:

113274

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00184

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000648

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

8946

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

4554

African (AFR)

AF:

0.00

AC:

AN:

128

American (AMR)

AF:

0.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AF:

0.00

AC:

AN:

790

European-Finnish (FIN)

AF:

0.00

AC:

AN:

170

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

7328

Other (OTH)

AF:

0.00

AC:

AN:

326

GnomAD4 genome

AF:

0.000521

AC:

AN:

113346

Hom.:

Cov.:

AF XY:

0.000448

AC XY:

AN XY:

53570

show subpopulations

African (AFR)

AF:

0.00184

AC:

AN:

28288

American (AMR)

AF:

0.000646

AC:

AN:

10828

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3116

East Asian (EAS)

AF:

0.00

AC:

AN:

3732

South Asian (SAS)

AF:

0.00

AC:

AN:

3262

European-Finnish (FIN)

AF:

0.00

AC:

AN:

3930

Middle Eastern (MID)

AF:

0.00

AC:

AN:

172

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

57932

Other (OTH)

AF:

0.00

AC:

AN:

1462

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.584

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-1.3

Splicing

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over