rs547206569

Variant names:

• chr7-45052050-CTAAG-C
• rs547206569
• NM_031443.4:c.205-11866_205-11863delAAGT

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_031443.4(CCM2):​c.205-11866_205-11863delAAGT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000873 in 152,326 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as not provided (no stars).

• Frequency: Genomes: 𝑓 0.00087 (0 hom., cov: 32)
• Consequence: CCM2 NM_031443.4 intron
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 0.519
• Publications: 0 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: Likely_benign. The variant received -5 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000873 (133/152326) while in subpopulation NFE AF = 0.00165 (112/68040). AF 95% confidence interval is 0.0014. There are 0 homozygotes in GnomAd4. There are 57 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 133 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCM2	NM_031443.4	c.205-11866_205-11863delAAGT		intron_variant	Intron 2 of 9	ENST00000258781.11	NP_113631.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCM2	ENST00000258781.11	c.205-11867_205-11864delTAAG		intron_variant	Intron 2 of 9	1	NM_031443.4	ENSP00000258781.7

Frequencies

GnomAD3 genomes AF: 0.000874 AC: 133 AN: 152208 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00165

Gnomad OTH AF: 0.000956

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.000873 AC: 133 AN: 152326 Hom.: 0 Cov.: 32 AF XY: 0.000765 AC XY: 57 AN XY: 74490

African (AFR) AF: 0.000265 AC: 11 AN: 41578

American (AMR) AF: 0.000262 AC: 4 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00165 AC: 112 AN: 68040

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00221 Hom.: 0

Bravo AF: 0.000733

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Cerebral cavernous malformation 2 Other:1

May 15, 2017

Institute of Human Genetics Greifswald, Research Division, University Medicine Greifswald

Significance: not provided

Review Status: no classification provided

Collection Method: research

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.52

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: rs547206569; hg19: chr7-45091649;