20-33667682-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001024675.2(ACTL10):​c.185C>T​(p.Ala62Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000048 in 1,459,408 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

ACTL10
NM_001024675.2 missense

Scores

9
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.11
Variant links:
Genes affected
ACTL10 (HGNC:16127): (actin like 10) Predicted to be part of dynactin complex. [provided by Alliance of Genome Resources, Apr 2022]
NECAB3 (HGNC:15851): (N-terminal EF-hand calcium binding protein 3) The protein encoded by this gene interacts with the amino-terminal domain of the neuron-specific X11-like protein (X11L), inhibits the association of X11L with amyloid precursor protein through a non-competitive mechanism, and abolishes the suppression of beta-amyloid production by X11L. This protein, together with X11L, may play an important role in the regulatory system of amyloid precursor protein metabolism and beta-amyloid generation. The protein is phosphorylated by NIMA-related expressed kinase 2, and localizes to the Golgi apparatus. Multiple 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 -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.21332416).
BS2
High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ACTL10NM_001024675.2 linkc.185C>T p.Ala62Val missense_variant Exon 1 of 1 ENST00000677665.1 NP_001019846.1 Q5JWF8
NECAB3NM_031232.4 linkc.387+1693G>A intron_variant Intron 5 of 11 ENST00000246190.11 NP_112509.3 Q96P71-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ACTL10ENST00000677665.1 linkc.185C>T p.Ala62Val missense_variant Exon 1 of 1 NM_001024675.2 ENSP00000504425.1 Q5JWF8
NECAB3ENST00000246190.11 linkc.387+1693G>A intron_variant Intron 5 of 11 5 NM_031232.4 ENSP00000246190.6 Q96P71-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000480
AC:
7
AN:
1459408
Hom.:
0
Cov.:
32
AF XY:
0.00000551
AC XY:
4
AN XY:
726048
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.0000195
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
33
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Mar 21, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.185C>T (p.A62V) alteration is located in exon 1 (coding exon 1) of the ACTL10 gene. This alteration results from a C to T substitution at nucleotide position 185, causing the alanine (A) at amino acid position 62 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Uncertain
0.082
D
BayesDel_noAF
Benign
-0.12
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.43
T
Eigen
Benign
-0.30
Eigen_PC
Benign
-0.34
FATHMM_MKL
Benign
0.091
N
LIST_S2
Benign
0.59
T
M_CAP
Uncertain
0.23
D
MetaRNN
Benign
0.21
T
MetaSVM
Uncertain
0.13
D
MutationAssessor
Uncertain
2.6
M
PrimateAI
Benign
0.39
T
PROVEAN
Benign
-1.3
N
REVEL
Uncertain
0.34
Sift
Uncertain
0.0020
D
Sift4G
Uncertain
0.060
T
Polyphen
0.51
P
Vest4
0.089
MVP
0.43
MPC
0.56
ClinPred
0.87
D
GERP RS
2.9
RBP_binding_hub_radar
1.1
RBP_regulation_power_radar
4.0
Varity_R
0.30
gMVP
0.35

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-32255488; COSMIC: COSV55778660; COSMIC: COSV55778660; API