rs2234767

Variant names:

• chr10-88989499-G-A
• rs2234767
• ENST00000690268.1:c.31G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-88989499-G-A
• chr10-88989499-G-T

Variant summary

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

The NM_001141945.3(ACTA2):​c.-24+1440C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.134 in 543,676 control chromosomes in the GnomAD database, including 6,468 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.11 (1426 hom., cov: 32)
  • Exomes 𝑓: 0.14 (5042 hom.)
• Consequence: ACTA2 NM_001141945.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: -0.866
• Publications: 216 publications found

Genes affected

FAS (HGNC:11920): (Fas cell surface death receptor) The protein encoded by this gene is a member of the TNF-receptor superfamily. This receptor contains a death domain. It has been shown to play a central role in the physiological regulation of programmed cell death, and has been implicated in the pathogenesis of various malignancies and diseases of the immune system. The interaction of this receptor with its ligand allows the formation of a death-inducing signaling complex that includes Fas-associated death domain protein (FADD), caspase 8, and caspase 10. The autoproteolytic processing of the caspases in the complex triggers a downstream caspase cascade, and leads to apoptosis. This receptor has been also shown to activate NF-kappaB, MAPK3/ERK1, and MAPK8/JNK, and is found to be involved in transducing the proliferating signals in normal diploid fibroblast and T cells. Several alternatively spliced transcript variants have been described, some of which are candidates for nonsense-mediated mRNA decay (NMD). The isoforms lacking the transmembrane domain may negatively regulate the apoptosis mediated by the full length isoform. [provided by RefSeq, Mar 2011]

ACTA2 (HGNC:130): (actin alpha 2, smooth muscle) This gene encodes one of six different actin proteins. Actins are highly conserved proteins that are involved in cell motility, structure, integrity, and intercellular signaling. The encoded protein is a smooth muscle actin that is involved in vascular contractility and blood pressure homeostasis. Mutations in this gene cause a variety of vascular diseases, such as thoracic aortic disease, coronary artery disease, stroke, and Moyamoya disease, as well as multisystemic smooth muscle dysfunction syndrome. [provided by RefSeq, Sep 2017]

ACTA2 Gene-Disease associations (from GenCC):

• multisystemic smooth muscle dysfunction syndrome

  Inheritance: AD, Unknown Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• aortic aneurysm, familial thoracic 6

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Moyamoya disease 5

  Inheritance: AD Classification: STRONG Submitted by: G2P, Genomics England PanelApp
• connective tissue disorder

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• familial thoracic aortic aneurysm and aortic dissection

  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 (REVEL=0.002).
• BP6: Variant 10-88989499-G-A is Benign according to our data. Variant chr10-88989499-G-A is described in ClinVar as Benign. ClinVar VariationId is 16517.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.406 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001141945.3. 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
	ACTA2	NM_001141945.3		c.-24+1440C>T		intron	N/A	NP_001135417.1	D2JYH4
	ACTA2	NM_001320855.2		c.-24+1523C>T		intron	N/A	NP_001307784.1	P62736
	ACTA2	NM_001406462.1		c.-182+1523C>T		intron	N/A	NP_001393391.1	P62736

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAS	ENST00000690268.1		c.31G>A	p.Ala11Thr	missense	Exon 3 of 11	ENSP00000509810.1	Q59FU8
	ACTA2	ENST00000415557.2	TSL:3	c.-24+1440C>T		intron	N/A	ENSP00000396730.2	P62736
	ACTA2	ENST00000458159.6	TSL:3	c.-24+1523C>T		intron	N/A	ENSP00000398239.2	P62736

Frequencies

GnomAD3 genomes AF: 0.114 AC: 17311 AN: 151962 Hom.: 1428 Cov.: 32

Gnomad AFR AF: 0.0470

Gnomad AMI AF: 0.0658

Gnomad AMR AF: 0.163

Gnomad ASJ AF: 0.123

Gnomad EAS AF: 0.420

Gnomad SAS AF: 0.188

Gnomad FIN AF: 0.121

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.113

Gnomad OTH AF: 0.129

GnomAD2 exomes AF: 0.151 AC: 34536 AN: 229260 AF XY: 0.149

Gnomad AFR exome AF: 0.0447

Gnomad AMR exome AF: 0.172

Gnomad ASJ exome AF: 0.114

Gnomad EAS exome AF: 0.425

Gnomad FIN exome AF: 0.120

Gnomad NFE exome AF: 0.112

Gnomad OTH exome AF: 0.139

GnomAD4 exome AF: 0.141 AC: 55307 AN: 391596 Hom.: 5042 Cov.: 0 AF XY: 0.142 AC XY: 31435 AN XY: 221656

African (AFR) AF: 0.0480 AC: 542 AN: 11292

American (AMR) AF: 0.171 AC: 6301 AN: 36810

Ashkenazi Jewish (ASJ) AF: 0.118 AC: 1581 AN: 13396

East Asian (EAS) AF: 0.423 AC: 7761 AN: 18348

South Asian (SAS) AF: 0.171 AC: 11427 AN: 66950

European-Finnish (FIN) AF: 0.116 AC: 1968 AN: 16922

Middle Eastern (MID) AF: 0.111 AC: 336 AN: 3014

European-Non Finnish (NFE) AF: 0.111 AC: 22877 AN: 206248

Other (OTH) AF: 0.135 AC: 2514 AN: 18616

GnomAD4 genome AF: 0.114 AC: 17313 AN: 152080 Hom.: 1426 Cov.: 32 AF XY: 0.118 AC XY: 8766 AN XY: 74356

African (AFR) AF: 0.0470 AC: 1948 AN: 41480

American (AMR) AF: 0.163 AC: 2500 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.123 AC: 426 AN: 3468

East Asian (EAS) AF: 0.420 AC: 2171 AN: 5166

South Asian (SAS) AF: 0.187 AC: 902 AN: 4816

European-Finnish (FIN) AF: 0.121 AC: 1280 AN: 10590

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.113 AC: 7703 AN: 67944

Other (OTH) AF: 0.130 AC: 275 AN: 2114

Alfa AF: 0.117 Hom.: 2462

Bravo AF: 0.112

Asia WGS AF: 0.327 AC: 1135 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)
-	-	-	LUNG CANCER, SUSCEPTIBILITY TO (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.31
DANN	Benign	0.50
PhyloP100		-0.87
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs2234767; hg19: chr10-90749256; COSMIC: COSV58238613;