Genetic Variant NM_031443.4:c.30+17G>T (chr7-45000380-G-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_031443.4(CCM2):c.30+17G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000661 in 1,286,624 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.000088 ( 0 hom., cov: 24)

Exomes 𝑓: 0.000063 ( 0 hom. )

Consequence

CCM2
NM_031443.4 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.30

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), 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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 7-45000380-G-T is Benign according to our data. Variant chr7-45000380-G-T is described in ClinVar as Benign. ClinVar VariationId is 261969.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000885 (13/146974) while in subpopulation SAS AF = 0.00279 (13/4654). AF 95% confidence interval is 0.00165. There are 0 homozygotes in GnomAd4. There are 12 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.

BS2

High AC in GnomAd4 at 13 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
CCM2	NM_031443.4	MANE Select	c.30+17G>T	intron	N/A	NP_113631.1
CCM2	NM_001363458.2		c.30+17G>T	intron	N/A	NP_001350387.1
CCM2	NM_001363459.2		c.30+17G>T	intron	N/A	NP_001350388.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
CCM2	ENST00000258781.11	TSL:1 MANE Select	c.30+17G>T	intron	N/A	ENSP00000258781.7
CCM2	ENST00000541586.5	TSL:3	c.30+17G>T	intron	N/A	ENSP00000444725.1
CCM2	ENST00000544363.5	TSL:3	c.30+17G>T	intron	N/A	ENSP00000438035.1

Frequencies

GnomAD3 genomes

AF:

0.0000885

AC:

AN:

146874

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00279

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000393

AC:

AN:

40754

AF XY:

0.000576

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

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:

0.0000632

AC:

AN:

1139650

Hom.:

Cov.:

AF XY:

0.0000802

AC XY:

AN XY:

548770

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23680

American (AMR)

AF:

0.00

AC:

AN:

13098

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16714

East Asian (EAS)

AF:

0.00

AC:

AN:

26838

South Asian (SAS)

AF:

0.00198

AC:

AN:

29858

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37196

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3128

European-Non Finnish (NFE)

AF:

0.00000212

AC:

AN:

943696

Other (OTH)

AF:

0.000242

AC:

AN:

45442

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

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:

0.0000885

AC:

AN:

146974

Hom.:

Cov.:

AF XY:

0.000168

AC XY:

AN XY:

71404

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

39966

American (AMR)

AF:

0.00

AC:

AN:

14678

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3426

East Asian (EAS)

AF:

0.00

AC:

AN:

4882

South Asian (SAS)

AF:

0.00279

AC:

AN:

4654

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9788

Middle Eastern (MID)

AF:

0.00

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

66374

Other (OTH)

AF:

0.00

AC:

AN:

2048

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.0000712

Hom.:

Bravo

AF:

0.0000227

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Jan 20, 2016

PreventionGenetics, part of Exact Sciences

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

-0.75

CADD

Benign

8.7

(source)

DANN

Benign

0.92

PhyloP100

1.3

PromoterAI

0.038

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(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