7-45000464-G-T

Variant names:

• chr7-45000464-G-T
• rs186517708
• NM_031443.4:c.30+101G>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_031443.4(CCM2):​c.30+101G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.085 in 187,022 control chromosomes in the GnomAD database, including 585 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.052 (304 hom., cov: 14)
  • Exomes 𝑓: 0.13 (281 hom.)
• Consequence: CCM2 NM_031443.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.32
• Publications: 2 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 7-45000464-G-T is Benign according to our data. Variant chr7-45000464-G-T is described in ClinVar as Benign. ClinVar VariationId is 1291962.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0671 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+101G>T		intron	N/A	NP_113631.1	Q9BSQ5-1
	CCM2	NM_001363458.2		c.30+101G>T		intron	N/A	NP_001350387.1
	CCM2	NM_001363459.2		c.30+101G>T		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+101G>T		intron	N/A	ENSP00000258781.7	Q9BSQ5-1
	CCM2	ENST00000938553.1		c.30+101G>T		intron	N/A	ENSP00000608612.1
	CCM2	ENST00000956241.1		c.30+101G>T		intron	N/A	ENSP00000626300.1

Frequencies

GnomAD3 genomes AF: 0.0520 AC: 5383 AN: 103608 Hom.: 304 Cov.: 14

Gnomad AFR AF: 0.0128

Gnomad AMI AF: 0.162

Gnomad AMR AF: 0.0520

Gnomad ASJ AF: 0.0774

Gnomad EAS AF: 0.00388

Gnomad SAS AF: 0.0189

Gnomad FIN AF: 0.105

Gnomad MID AF: 0.0607

Gnomad NFE AF: 0.0691

Gnomad OTH AF: 0.0552

GnomAD4 exome AF: 0.126 AC: 10510 AN: 83380 Hom.: 281 AF XY: 0.126 AC XY: 5359 AN XY: 42442

African (AFR) AF: 0.0415 AC: 72 AN: 1736

American (AMR) AF: 0.101 AC: 216 AN: 2140

Ashkenazi Jewish (ASJ) AF: 0.128 AC: 401 AN: 3124

East Asian (EAS) AF: 0.0904 AC: 835 AN: 9232

South Asian (SAS) AF: 0.0366 AC: 24 AN: 656

European-Finnish (FIN) AF: 0.154 AC: 1229 AN: 7962

Middle Eastern (MID) AF: 0.118 AC: 50 AN: 422

European-Non Finnish (NFE) AF: 0.133 AC: 7016 AN: 52872

Other (OTH) AF: 0.127 AC: 667 AN: 5236

GnomAD4 genome AF: 0.0519 AC: 5381 AN: 103642 Hom.: 304 Cov.: 14 AF XY: 0.0527 AC XY: 2577 AN XY: 48938

African (AFR) AF: 0.0128 AC: 341 AN: 26696

American (AMR) AF: 0.0521 AC: 537 AN: 10312

Ashkenazi Jewish (ASJ) AF: 0.0774 AC: 209 AN: 2700

East Asian (EAS) AF: 0.00389 AC: 13 AN: 3344

South Asian (SAS) AF: 0.0186 AC: 51 AN: 2736

European-Finnish (FIN) AF: 0.105 AC: 578 AN: 5524

Middle Eastern (MID) AF: 0.0670 AC: 13 AN: 194

European-Non Finnish (NFE) AF: 0.0691 AC: 3460 AN: 50106

Other (OTH) AF: 0.0554 AC: 78 AN: 1408

Alfa AF: 0.0237 Hom.: 43

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
BayesDel_noAF	Benign	-0.80
CADD	Benign	8.1
DANN	Benign	0.84
PhyloP100		-2.3
PromoterAI		0.0027	Neutral
RBP_binding_hub_radar		0.77
RBP_regulation_power_radar		3.3
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: rs186517708; hg19: chr7-45040063;