chr7-45000161-G-GGGCCTGCTCT

Variant names:

• chr7-45000161-G-GGGCCTGCTCT
• rs3070689
• ENST00000461377.5:n.383+304_383+305insGGCCTGCTCT

Variant summary

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

The NR_030770.2(CCM2):​n.112+304_112+305insGGCCTGCTCT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 1.0 (56376 hom., cov: 0)
  • Exomes 𝑓: 0.99 (4423 hom.)
  • Failed GnomAD Quality Control
• Consequence: CCM2 NR_030770.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.25
• 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

ENSG00000309655 (HGNC:):

ACMG classification

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

• BP6: Variant 7-45000161-G-GGGCCTGCTCT is Benign according to our data. Variant chr7-45000161-G-GGGCCTGCTCT is described in ClinVar as Benign. ClinVar VariationId is 1266041.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.991 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NR_030770.2. 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	NR_030770.2		n.112+304_112+305insGGCCTGCTCT		intron	N/A
	CCM2	NM_031443.4	MANE Select	c.-173_-172insGGCCTGCTCT		upstream_gene	N/A	NP_113631.1	Q9BSQ5-1
	CCM2	NM_001363458.2		c.-173_-172insGGCCTGCTCT		upstream_gene	N/A	NP_001350387.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCM2	ENST00000461377.5	TSL:5	n.383+304_383+305insGGCCTGCTCT		intron	N/A
	CCM2	ENST00000258781.11	TSL:1 MANE Select	c.-173_-172insGGCCTGCTCT		upstream_gene	N/A	ENSP00000258781.7	Q9BSQ5-1
	CCM2	ENST00000938553.1		c.-173_-172insGGCCTGCTCT		upstream_gene	N/A	ENSP00000608612.1

Frequencies

GnomAD3 genomes AF: 0.997 AC: 112967 AN: 113264 Hom.: 56339 Cov.: 0

Gnomad AFR AF: 0.997

Gnomad AMI AF: 0.998

Gnomad AMR AF: 0.998

Gnomad ASJ AF: 0.999

Gnomad EAS AF: 0.998

Gnomad SAS AF: 0.999

Gnomad FIN AF: 0.998

Gnomad MID AF: 1.00

Gnomad NFE AF: 0.997

Gnomad OTH AF: 0.996

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.994 AC: 8894 AN: 8944 Hom.: 4423 Cov.: 3 AF XY: 0.996 AC XY: 4535 AN XY: 4554

African (AFR) AF: 1.00 AC: 128 AN: 128

American (AMR) AF: 1.00 AC: 54 AN: 54

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 86 AN: 86

East Asian (EAS) AF: 1.00 AC: 46 AN: 46

South Asian (SAS) AF: 0.992 AC: 784 AN: 790

European-Finnish (FIN) AF: 0.994 AC: 169 AN: 170

Middle Eastern (MID) AF: 1.00 AC: 18 AN: 18

European-Non Finnish (NFE) AF: 0.995 AC: 7286 AN: 7326

Other (OTH) AF: 0.991 AC: 323 AN: 326

GnomAD4 genome AF: 0.997 AC: 113040 AN: 113336 Hom.: 56376 Cov.: 0 AF XY: 0.998 AC XY: 53440 AN XY: 53564

African (AFR) AF: 0.997 AC: 28189 AN: 28282

American (AMR) AF: 0.998 AC: 10804 AN: 10830

Ashkenazi Jewish (ASJ) AF: 0.999 AC: 3114 AN: 3116

East Asian (EAS) AF: 0.998 AC: 3723 AN: 3732

South Asian (SAS) AF: 0.999 AC: 3256 AN: 3258

European-Finnish (FIN) AF: 0.998 AC: 3923 AN: 3930

Middle Eastern (MID) AF: 1.00 AC: 172 AN: 172

European-Non Finnish (NFE) AF: 0.997 AC: 57779 AN: 57930

Other (OTH) AF: 0.997 AC: 1457 AN: 1462

Alfa AF: 0.00 Hom.: 0

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		-1.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs3070689; hg19: chr7-45039760;