chr7-45000161-G-GTGCCTGCTCT

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NR_030770.2(CCM2):​n.112+304_112+305insTGCCTGCTCT variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00052 (3 hom., cov: 0)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CCM2 NR_030770.2 intron
• Clinical Significance: Not reported in ClinVar
• 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 -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000521 (59/113346) while in subpopulation AFR AF = 0.00184 (52/28288). AF 95% confidence interval is 0.00144. There are 3 homozygotes in GnomAd4. There are 24 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 59 AD gene.

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+305insTGCCTGCTCT		intron	N/A
	CCM2	NM_031443.4	MANE Select	c.-173_-172insTGCCTGCTCT		upstream_gene	N/A	NP_113631.1	Q9BSQ5-1
	CCM2	NM_001363458.2		c.-173_-172insTGCCTGCTCT		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+305insTGCCTGCTCT		intron	N/A
	CCM2	ENST00000258781.11	TSL:1 MANE Select	c.-173_-172insTGCCTGCTCT		upstream_gene	N/A	ENSP00000258781.7	Q9BSQ5-1
	CCM2	ENST00000938553.1		c.-173_-172insTGCCTGCTCT		upstream_gene	N/A	ENSP00000608612.1

Frequencies

GnomAD3 genomes AF: 0.000521 AC: 59 AN: 113274 Hom.: 3 Cov.: 0

Gnomad AFR AF: 0.00184

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000648

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 8946 Hom.: 0 Cov.: 3 AF XY: 0.00 AC XY: 0 AN XY: 4554

African (AFR) AF: 0.00 AC: 0 AN: 128

American (AMR) AF: 0.00 AC: 0 AN: 54

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 86

East Asian (EAS) AF: 0.00 AC: 0 AN: 46

South Asian (SAS) AF: 0.00 AC: 0 AN: 790

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 170

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 18

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 7328

Other (OTH) AF: 0.00 AC: 0 AN: 326

GnomAD4 genome AF: 0.000521 AC: 59 AN: 113346 Hom.: 3 Cov.: 0 AF XY: 0.000448 AC XY: 24 AN XY: 53570

African (AFR) AF: 0.00184 AC: 52 AN: 28288

American (AMR) AF: 0.000646 AC: 7 AN: 10828

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3116

East Asian (EAS) AF: 0.00 AC: 0 AN: 3732

South Asian (SAS) AF: 0.00 AC: 0 AN: 3262

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3930

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 172

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 57932

Other (OTH) AF: 0.00 AC: 0 AN: 1462

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.3

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;