rs564132631

Variant names:

• chr7-45040466-T-C
• rs564132631
• NM_031443.4:c.204+2040T>C

Your query was ambiguous. Multiple possible variants found:

• chr7-45040466-T-C
• chr7-45040466-T-G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_031443.4(CCM2):​c.204+2040T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000107 in 150,130 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 not provided (no stars).

• Frequency: Genomes: 𝑓 0.00011 (0 hom., cov: 33)
• Consequence: CCM2 NM_031443.4 intron
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 0.978
• 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000107 (16/150130) while in subpopulation NFE AF = 0.000193 (13/67486). AF 95% confidence interval is 0.000113. There are 0 homozygotes in GnomAd4. There are 8 alleles in the male GnomAd4 subpopulation. Median coverage is 33. 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 16 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCM2	NM_031443.4	MANE Select	c.204+2040T>C		intron	N/A	NP_113631.1
	CCM2	NM_001363458.2		c.204+2040T>C		intron	N/A	NP_001350387.1
	CCM2	NM_001029835.2		c.267+2040T>C		intron	N/A	NP_001025006.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCM2	ENST00000258781.11	TSL:1 MANE Select	c.204+2040T>C		intron	N/A	ENSP00000258781.7
	CCM2	ENST00000938553.1		c.369+2040T>C		intron	N/A	ENSP00000608612.1
	CCM2	ENST00000956241.1		c.204+2040T>C		intron	N/A	ENSP00000626300.1

Frequencies

GnomAD3 genomes AF: 0.000107 AC: 16 AN: 150130 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000734

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000193

Gnomad OTH AF: 0.00

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

GnomAD4 genome AF: 0.000107 AC: 16 AN: 150130 Hom.: 0 Cov.: 33 AF XY: 0.000109 AC XY: 8 AN XY: 73192

African (AFR) AF: 0.0000734 AC: 3 AN: 40896

American (AMR) AF: 0.00 AC: 0 AN: 15078

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3438

East Asian (EAS) AF: 0.00 AC: 0 AN: 5062

South Asian (SAS) AF: 0.00 AC: 0 AN: 4670

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10216

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000193 AC: 13 AN: 67486

Other (OTH) AF: 0.00 AC: 0 AN: 2064

Alfa AF: 0.000159 Hom.: 0

Bravo AF: 0.0000831

ClinVar

ClinVar submissions as Germline

Significance: not provided

Revision: no classification provided

Pathogenic	VUS	Benign	Condition
-	-	-	Cerebral cavernous malformation 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.44
DANN	Benign	0.77
PhyloP100		0.98

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: rs564132631; hg19: chr7-45080065;