rs190686229

Variant names:

• chr7-45074420-C-T
• rs190686229
• NM_031443.4:c.1054+12C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000258781.11(CCM2):​c.1054+12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00421 in 1,610,342 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0044 (18 hom.)
• Consequence: CCM2 ENST00000258781.11 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.296
• Publications: 1 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 7-45074420-C-T is Benign according to our data. Variant chr7-45074420-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261964.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0024 (366/152318) while in subpopulation NFE AF = 0.00429 (292/68016). AF 95% confidence interval is 0.00389. There are 0 homozygotes in GnomAd4. There are 156 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 366 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000258781.11. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCM2	NM_031443.4	MANE Select	c.1054+12C>T		intron	N/A	NP_113631.1
	CCM2	NM_001363458.2		c.1177+12C>T		intron	N/A	NP_001350387.1
	CCM2	NM_001029835.2		c.1117+12C>T		intron	N/A	NP_001025006.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCM2	ENST00000258781.11	TSL:1 MANE Select	c.1054+12C>T		intron	N/A	ENSP00000258781.7
	CCM2	ENST00000477605.1	TSL:1	n.1389+12C>T		intron	N/A
	CCM2	ENST00000481194.1	TSL:1	n.4627+12C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00240 AC: 366 AN: 152200 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000844

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000850

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00429

Gnomad OTH AF: 0.00334

GnomAD2 exomes AF: 0.00256 AC: 628 AN: 245106 AF XY: 0.00279

Gnomad AFR exome AF: 0.00116

Gnomad AMR exome AF: 0.00141

Gnomad ASJ exome AF: 0.00464

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000189

Gnomad NFE exome AF: 0.00420

Gnomad OTH exome AF: 0.00217

GnomAD4 exome AF: 0.00440 AC: 6412 AN: 1458024 Hom.: 18 Cov.: 30 AF XY: 0.00433 AC XY: 3140 AN XY: 725196

African (AFR) AF: 0.000898 AC: 30 AN: 33402

American (AMR) AF: 0.00133 AC: 59 AN: 44418

Ashkenazi Jewish (ASJ) AF: 0.00545 AC: 142 AN: 26070

East Asian (EAS) AF: 0.00 AC: 0 AN: 39582

South Asian (SAS) AF: 0.00130 AC: 112 AN: 85842

European-Finnish (FIN) AF: 0.000360 AC: 19 AN: 52738

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00522 AC: 5798 AN: 1109948

Other (OTH) AF: 0.00418 AC: 252 AN: 60264

GnomAD4 genome AF: 0.00240 AC: 366 AN: 152318 Hom.: 0 Cov.: 33 AF XY: 0.00209 AC XY: 156 AN XY: 74488

African (AFR) AF: 0.000842 AC: 35 AN: 41572

American (AMR) AF: 0.000849 AC: 13 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00429 AC: 292 AN: 68016

Other (OTH) AF: 0.00331 AC: 7 AN: 2116

Alfa AF: 0.00337 Hom.: 0

Bravo AF: 0.00254

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Cerebral cavernous malformation 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.77
DANN	Benign	0.41
PhyloP100		0.30
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs190686229; hg19: chr7-45114019;