Genetic Variant NM_031443.4:c.30+6C>T (chr7-45000369-C-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_031443.4(CCM2):c.30+6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000271 in 1,292,222 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000021 ( 0 hom., cov: 24)

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

CCM2
NM_031443.4 splice_region, intron

Scores

Splicing: ADA: 0.00003793

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.723

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.72).

BP6

Variant 7-45000369-C-T is Benign according to our data. Variant chr7-45000369-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 517106.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAdExome4 at 32 AD gene.

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+6C>T	splice_region intron	N/A	NP_113631.1	Q9BSQ5-1
CCM2	NM_001363458.2		c.30+6C>T	splice_region intron	N/A	NP_001350387.1
CCM2	NM_001363459.2		c.30+6C>T	splice_region 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+6C>T	splice_region intron	N/A	ENSP00000258781.7	Q9BSQ5-1
CCM2	ENST00000938553.1		c.30+6C>T	splice_region intron	N/A	ENSP00000608612.1
CCM2	ENST00000956241.1		c.30+6C>T	splice_region intron	N/A	ENSP00000626300.1

Frequencies

GnomAD3 genomes

AF:

0.0000207

AC:

AN:

144882

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000883

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

GnomAD2 exomes

AF:

0.0000195

AC:

AN:

51162

AF XY:

0.0000350

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000262

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000279

AC:

AN:

1147340

Hom.:

Cov.:

AF XY:

0.0000379

AC XY:

AN XY:

553564

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23920

American (AMR)

AF:

0.00

AC:

AN:

14680

Ashkenazi Jewish (ASJ)

AF:

0.00109

AC:

AN:

17436

East Asian (EAS)

AF:

0.00

AC:

AN:

26620

South Asian (SAS)

AF:

0.00

AC:

AN:

31842

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37456

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3150

European-Non Finnish (NFE)

AF:

0.0000116

AC:

AN:

946486

Other (OTH)

AF:

0.0000437

AC:

AN:

45750

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.447

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.0000207

AC:

AN:

144882

Hom.:

Cov.:

AF XY:

0.0000142

AC XY:

AN XY:

70288

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

39392

American (AMR)

AF:

0.00

AC:

AN:

14458

Ashkenazi Jewish (ASJ)

AF:

0.000883

AC:

AN:

3396

East Asian (EAS)

AF:

0.00

AC:

AN:

4752

South Asian (SAS)

AF:

0.00

AC:

AN:

4512

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9394

Middle Eastern (MID)

AF:

0.00

AC:

AN:

296

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

65806

Other (OTH)

AF:

0.00

AC:

AN:

2002

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.0000683

Hom.:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

(source)

DANN

Benign

0.97

PhyloP100

-0.72

PromoterAI

-0.035

Neutral

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000038

dbscSNV1_RF

Benign

0.0

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

Computational scores

Splicing

Publications

Other links and lift over