rs1403112546

Variant names:

• chr7-45000457-G-GC
• rs1403112546
• NM_031443.4:c.30+94_30+95insC

Your query was ambiguous. Multiple possible variants found:

• chr7-45000457-G-GC
• chr7-45000457-G-GA
• chr7-45000457-G-GT

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+94_30+95insC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0356 in 337,280 control chromosomes in the GnomAD database, including 513 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.041 (251 hom., cov: 19)
  • Exomes 𝑓: 0.032 (262 hom.)
• Consequence: CCM2 NM_031443.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.188
• 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), 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 7-45000457-G-GC is Benign according to our data. Variant chr7-45000457-G-GC is described in ClinVar as Benign. ClinVar VariationId is 1224029.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.057 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+94_30+95insC		intron	N/A	NP_113631.1	Q9BSQ5-1
	CCM2	NM_001363458.2		c.30+94_30+95insC		intron	N/A	NP_001350387.1
	CCM2	NM_001363459.2		c.30+94_30+95insC		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+94_30+95insC		intron	N/A	ENSP00000258781.7	Q9BSQ5-1
	CCM2	ENST00000938553.1		c.30+94_30+95insC		intron	N/A	ENSP00000608612.1
	CCM2	ENST00000956241.1		c.30+94_30+95insC		intron	N/A	ENSP00000626300.1

Frequencies

GnomAD3 genomes AF: 0.0415 AC: 5064 AN: 121998 Hom.: 251 Cov.: 19

Gnomad AFR AF: 0.00952

Gnomad AMI AF: 0.152

Gnomad AMR AF: 0.0395

Gnomad ASJ AF: 0.0715

Gnomad EAS AF: 0.00107

Gnomad SAS AF: 0.0118

Gnomad FIN AF: 0.0661

Gnomad MID AF: 0.0368

Gnomad NFE AF: 0.0587

Gnomad OTH AF: 0.0498

GnomAD4 exome AF: 0.0323 AC: 6943 AN: 215204 Hom.: 262 AF XY: 0.0331 AC XY: 3592 AN XY: 108376

African (AFR) AF: 0.00902 AC: 39 AN: 4322

American (AMR) AF: 0.0285 AC: 135 AN: 4736

Ashkenazi Jewish (ASJ) AF: 0.0521 AC: 328 AN: 6292

East Asian (EAS) AF: 0.00 AC: 0 AN: 18184

South Asian (SAS) AF: 0.00320 AC: 8 AN: 2498

European-Finnish (FIN) AF: 0.0628 AC: 904 AN: 14386

Middle Eastern (MID) AF: 0.0305 AC: 29 AN: 950

European-Non Finnish (NFE) AF: 0.0333 AC: 5049 AN: 151644

Other (OTH) AF: 0.0370 AC: 451 AN: 12192

GnomAD4 genome AF: 0.0415 AC: 5062 AN: 122076 Hom.: 251 Cov.: 19 AF XY: 0.0412 AC XY: 2426 AN XY: 58932

African (AFR) AF: 0.00950 AC: 313 AN: 32964

American (AMR) AF: 0.0396 AC: 513 AN: 12970

Ashkenazi Jewish (ASJ) AF: 0.0715 AC: 211 AN: 2950

East Asian (EAS) AF: 0.00107 AC: 4 AN: 3728

South Asian (SAS) AF: 0.0119 AC: 41 AN: 3458

European-Finnish (FIN) AF: 0.0661 AC: 553 AN: 8364

Middle Eastern (MID) AF: 0.0397 AC: 10 AN: 252

European-Non Finnish (NFE) AF: 0.0587 AC: 3234 AN: 55102

Other (OTH) AF: 0.0492 AC: 79 AN: 1606

Alfa AF: 0.0153 Hom.: 34

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		-0.19
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: rs1403112546; hg19: chr7-45040056;