14-68874917-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2

The NM_001130004.2(ACTN1):​c.2687C>T​(p.Pro896Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,459,162 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000055 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

ACTN1
NM_001130004.2 missense

Scores

4
11
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 10.0
Variant links:
Genes affected
ACTN1 (HGNC:163): (actinin alpha 1) Alpha actinins belong to the spectrin gene superfamily which represents a diverse group of cytoskeletal proteins, including the alpha and beta spectrins and dystrophins. Alpha actinin is an actin-binding protein with multiple roles in different cell types. In nonmuscle cells, the cytoskeletal isoform is found along microfilament bundles and adherens-type junctions, where it is involved in binding actin to the membrane. In contrast, skeletal, cardiac, and smooth muscle isoforms are localized to the Z-disc and analogous dense bodies, where they help anchor the myofibrillar actin filaments. This gene encodes a nonmuscle, cytoskeletal, alpha actinin isoform and maps to the same site as the structurally similar erythroid beta spectrin gene. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ACTN1. . Gene score misZ: 3.3621 (greater than the threshold 3.09). Trascript score misZ: 5.1933 (greater than threshold 3.09). The gene has 22 curated pathogenic missense variants (we use a threshold of 10). The gene has 8 curated benign missense variants. GenCC has associacion of the gene with autosomal dominant macrothrombocytopenia, platelet-type bleeding disorder 15.
BS2
High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ACTN1NM_001130004.2 linkc.2687C>T p.Pro896Leu missense_variant 22/22 ENST00000394419.9 NP_001123476.1 P12814-3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ACTN1ENST00000394419.9 linkc.2687C>T p.Pro896Leu missense_variant 22/221 NM_001130004.2 ENSP00000377941.4 P12814-3

Frequencies

GnomAD3 genomes
AF:
0.00
AC:
0
AN:
152208
Hom.:
0
Cov.:
33
FAILED QC
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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
GnomAD3 exomes
AF:
0.0000240
AC:
6
AN:
249562
Hom.:
0
AF XY:
0.0000148
AC XY:
2
AN XY:
135140
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000174
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000548
AC:
8
AN:
1459162
Hom.:
0
Cov.:
31
AF XY:
0.00000276
AC XY:
2
AN XY:
725396
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000179
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
152208
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74358
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 24, 2024This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 896 of the ACTN1 protein (p.Pro896Leu). This variant is present in population databases (rs757078973, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with ACTN1-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
0.0061
T
BayesDel_noAF
Uncertain
0.040
CADD
Pathogenic
27
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.44
T;.;.;T;.
Eigen
Uncertain
0.57
Eigen_PC
Uncertain
0.60
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.90
D;D;D;D;D
M_CAP
Benign
0.044
D
MetaRNN
Uncertain
0.60
D;D;D;D;D
MetaSVM
Uncertain
-0.22
T
MutationAssessor
Uncertain
2.1
M;.;.;.;.
PrimateAI
Pathogenic
0.82
D
PROVEAN
Pathogenic
-5.9
D;D;D;D;D
REVEL
Uncertain
0.38
Sift
Uncertain
0.013
D;D;D;D;D
Sift4G
Uncertain
0.044
D;D;D;D;D
Polyphen
0.0030
B;.;B;.;.
Vest4
0.67
MVP
0.79
MPC
0.039
ClinPred
0.60
D
GERP RS
4.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.32
gMVP
0.60

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs757078973; hg19: chr14-69341634; API