dbSNP rs397517071: ACTC1:p.Ile269Thr (chr15-34792092-A-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PM2PP3PP5

The NM_005159.5(ACTC1):c.806T>C(p.Ile269Thr) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)

Consequence

ACTC1
NM_005159.5 missense, splice_region

Scores

Splicing: ADA: 0.002350

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:2

Conservation

PhyloP100: 9.32

Publications

3 publications found

Variant links:

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]

ACTC1 links:

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

GJD2-DT links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_005159.5

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.813

PP5

Variant 15-34792092-A-G is Pathogenic according to our data. Variant chr15-34792092-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45190.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ACTC1	NM_005159.5	MANE Select	c.806T>C	p.Ile269Thr	missense splice_region	Exon 5 of 7	NP_005150.1	P68032
ACTC1	NM_001406482.1		c.806T>C	p.Ile269Thr	missense splice_region	Exon 4 of 6	NP_001393411.1	P68032
ACTC1	NM_001406483.1		c.806T>C	p.Ile269Thr	missense splice_region	Exon 5 of 7	NP_001393412.1	P68032

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ACTC1	ENST00000290378.6	TSL:1 MANE Select	c.806T>C	p.Ile269Thr	missense splice_region	Exon 5 of 7	ENSP00000290378.4	P68032
ACTC1	ENST00000713613.1		c.917T>C	p.Ile306Thr	missense splice_region	Exon 6 of 8	ENSP00000518909.1	A0AAQ5BGG2
ACTC1	ENST00000868408.1		c.812T>C	p.Ile271Thr	missense splice_region	Exon 5 of 7	ENSP00000538467.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Hypertrophic cardiomyopathy 11;C2748552:Atrial septal defect 5;C3150681:Dilated cardiomyopathy 1R (1)

Primary dilated cardiomyopathy;C1960469:Left ventricular noncompaction (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.46

CardioboostCm

Uncertain

0.80

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

(source)

DANN

Benign

0.94

DEOGEN2

Pathogenic

0.94

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.95

M_CAP

Pathogenic

0.38

MetaRNN

Pathogenic

0.81

MetaSVM

Pathogenic

0.99

MutationAssessor

Uncertain

2.9

PhyloP100

9.3

PrimateAI

Pathogenic

0.87

PROVEAN

Uncertain

-2.9

REVEL

Pathogenic

0.87

Sift4G

Uncertain

0.026

Polyphen

0.0070

Vest4

0.85

MutPred

0.57

Loss of stability (P = 0.0174)

MVP

0.99

MPC

1.9

ClinPred

0.99

GERP RS

4.7

Varity_R

0.86

gMVP

0.98

Mutation Taster

=20/80

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0023

dbscSNV1_RF

Benign

0.024

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over