chr7-45000464-G-GT

Variant names:

• chr7-45000464-G-GT
• rs558165400
• NM_031443.4:c.30+101_30+102insT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_031443.4(CCM2):​c.30+101_30+102insT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.459 in 189,776 control chromosomes in the GnomAD database, including 18,301 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.40 (9774 hom., cov: 0)
  • Exomes 𝑓: 0.53 (8527 hom.)
• Consequence: CCM2 NM_031443.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.570
• 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), ClinGen, Genomics England PanelApp
• famililal cerebral cavernous malformations

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP6: Variant 7-45000464-G-GT is Benign according to our data. Variant chr7-45000464-G-GT is described in ClinVar as Benign. ClinVar VariationId is 1222839.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.684 is higher than 0.05.

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.30+101_30+102insT		intron	N/A	NP_113631.1	Q9BSQ5-1
	CCM2	NM_001363458.2		c.30+101_30+102insT		intron	N/A	NP_001350387.1
	CCM2	NM_001363459.2		c.30+101_30+102insT		intron	N/A	NP_001350388.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCM2	ENST00000258781.11	TSL:1 MANE Select	c.30+101_30+102insT		intron	N/A	ENSP00000258781.7	Q9BSQ5-1
	CCM2	ENST00000938553.1		c.30+101_30+102insT		intron	N/A	ENSP00000608612.1
	CCM2	ENST00000956241.1		c.30+101_30+102insT		intron	N/A	ENSP00000626300.1

Frequencies

GnomAD3 genomes AF: 0.403 AC: 41661 AN: 103462 Hom.: 9779 Cov.: 0

Gnomad AFR AF: 0.165

Gnomad AMI AF: 0.524

Gnomad AMR AF: 0.407

Gnomad ASJ AF: 0.452

Gnomad EAS AF: 0.709

Gnomad SAS AF: 0.412

Gnomad FIN AF: 0.542

Gnomad MID AF: 0.463

Gnomad NFE AF: 0.486

Gnomad OTH AF: 0.425

GnomAD4 exome AF: 0.527 AC: 45489 AN: 86280 Hom.: 8527 AF XY: 0.525 AC XY: 23056 AN XY: 43930

African (AFR) AF: 0.309 AC: 542 AN: 1756

American (AMR) AF: 0.483 AC: 1052 AN: 2180

Ashkenazi Jewish (ASJ) AF: 0.503 AC: 1599 AN: 3180

East Asian (EAS) AF: 0.650 AC: 6372 AN: 9810

South Asian (SAS) AF: 0.485 AC: 330 AN: 680

European-Finnish (FIN) AF: 0.554 AC: 4583 AN: 8280

Middle Eastern (MID) AF: 0.507 AC: 218 AN: 430

European-Non Finnish (NFE) AF: 0.515 AC: 28071 AN: 54546

Other (OTH) AF: 0.502 AC: 2722 AN: 5418

GnomAD4 genome AF: 0.402 AC: 41645 AN: 103496 Hom.: 9774 Cov.: 0 AF XY: 0.402 AC XY: 19631 AN XY: 48890

African (AFR) AF: 0.165 AC: 4404 AN: 26662

American (AMR) AF: 0.407 AC: 4185 AN: 10290

Ashkenazi Jewish (ASJ) AF: 0.452 AC: 1218 AN: 2692

East Asian (EAS) AF: 0.708 AC: 2364 AN: 3338

South Asian (SAS) AF: 0.413 AC: 1128 AN: 2732

European-Finnish (FIN) AF: 0.542 AC: 3014 AN: 5556

Middle Eastern (MID) AF: 0.448 AC: 87 AN: 194

European-Non Finnish (NFE) AF: 0.486 AC: 24324 AN: 50010

Other (OTH) AF: 0.425 AC: 597 AN: 1404

Alfa AF: 0.233 Hom.: 645

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.57
Mutation Taster		=100/0	polymorphism (auto)

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: rs558165400; hg19: chr7-45040063; COSMIC: COSV51848404;