rs2307493

Variant names:

• chr15-34791177-A-G
• rs2307493
• NM_005159.5:c.927T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005159.5(ACTC1):​c.927T>C​(p.Pro309Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00736 in 1,613,710 control chromosomes in the GnomAD database, including 245 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P309P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.023 (111 hom., cov: 32)
  • Exomes 𝑓: 0.0057 (134 hom.)
• Consequence: ACTC1 NM_005159.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 1.36
• Publications: 3 publications found

Genes affected

ACTC1 (HGNC:143): (actin alpha cardiac muscle 1) Actins are highly conserved proteins that are involved in various types of cell motility. Polymerization of globular actin (G-actin) leads to a structural filament (F-actin) in the form of a two-stranded helix. Each actin can bind to four others. The protein encoded by this gene belongs to the actin family which is comprised of three main groups of actin isoforms, alpha, beta, and gamma. The alpha actins are found in muscle tissues and are a major constituent of the contractile apparatus. Defects in this gene have been associated with idiopathic dilated cardiomyopathy (IDC) and familial hypertrophic cardiomyopathy (FHC). [provided by RefSeq, Jul 2008]

GJD2-DT (HGNC:55560): (GJD2 divergent transcript)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 15-34791177-A-G is Benign according to our data. Variant chr15-34791177-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 45194.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.36 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0702 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005159.5. 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
	ACTC1	NM_005159.5	MANE Select	c.927T>C	p.Pro309Pro	synonymous	Exon 6 of 7	NP_005150.1
	ACTC1	NM_001406482.1		c.927T>C	p.Pro309Pro	synonymous	Exon 5 of 6	NP_001393411.1
	ACTC1	NM_001406483.1		c.927T>C	p.Pro309Pro	synonymous	Exon 6 of 7	NP_001393412.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTC1	ENST00000290378.6	TSL:1 MANE Select	c.927T>C	p.Pro309Pro	synonymous	Exon 6 of 7	ENSP00000290378.4
	ACTC1	ENST00000713613.1		c.1038T>C	p.Pro346Pro	synonymous	Exon 7 of 8	ENSP00000518909.1
	ACTC1	ENST00000868408.1		c.933T>C	p.Pro311Pro	synonymous	Exon 6 of 7	ENSP00000538467.1

Frequencies

GnomAD3 genomes AF: 0.0230 AC: 3494 AN: 152142 Hom.: 110 Cov.: 32

Gnomad AFR AF: 0.0722

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00930

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0159

Gnomad NFE AF: 0.00451

Gnomad OTH AF: 0.0162

GnomAD2 exomes AF: 0.00829 AC: 2083 AN: 251394 AF XY: 0.00655

Gnomad AFR exome AF: 0.0751

Gnomad AMR exome AF: 0.00882

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.000707

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00384

Gnomad OTH exome AF: 0.0108

GnomAD4 exome AF: 0.00572 AC: 8361 AN: 1461450 Hom.: 134 Cov.: 31 AF XY: 0.00537 AC XY: 3907 AN XY: 726922

African (AFR) AF: 0.0770 AC: 2579 AN: 33472

American (AMR) AF: 0.00901 AC: 403 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.000497 AC: 13 AN: 26132

East Asian (EAS) AF: 0.000277 AC: 11 AN: 39682

South Asian (SAS) AF: 0.00126 AC: 109 AN: 86244

European-Finnish (FIN) AF: 0.000281 AC: 15 AN: 53416

Middle Eastern (MID) AF: 0.0158 AC: 91 AN: 5766

European-Non Finnish (NFE) AF: 0.00416 AC: 4622 AN: 1111638

Other (OTH) AF: 0.00858 AC: 518 AN: 60380

GnomAD4 genome AF: 0.0231 AC: 3511 AN: 152260 Hom.: 111 Cov.: 32 AF XY: 0.0223 AC XY: 1659 AN XY: 74454

African (AFR) AF: 0.0724 AC: 3007 AN: 41536

American (AMR) AF: 0.00928 AC: 142 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5186

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.0171 AC: 5 AN: 292

European-Non Finnish (NFE) AF: 0.00451 AC: 307 AN: 68030

Other (OTH) AF: 0.0165 AC: 35 AN: 2116

Alfa AF: 0.0155 Hom.: 56

Bravo AF: 0.0266

Asia WGS AF: 0.00751 AC: 26 AN: 3478

EpiCase AF: 0.00469

EpiControl AF: 0.00397

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	3	not provided (3)
-	-	2	Cardiomyopathy (2)
-	-	2	Hypertrophic cardiomyopathy (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1R (1)
-	-	1	Hypertrophic cardiomyopathy 11 (1)
-	-	1	Hypertrophic cardiomyopathy 11;C2748552:Atrial septal defect 5;C3150681:Dilated cardiomyopathy 1R (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	11
DANN	Benign	0.76
PhyloP100		1.4
Mutation Taster		=85/15	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: rs2307493; hg19: chr15-35083378;