5-57482175-C-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2

The NM_001017992.4(ACTBL2):​c.533G>T​(p.Arg178Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000013 in 1,614,052 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

ACTBL2
NM_001017992.4 missense

Scores

10
5
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.07
Variant links:
Genes affected
ACTBL2 (HGNC:17780): (actin beta like 2) Predicted to enable protein kinase binding activity. Predicted to be a structural constituent of postsynaptic actin cytoskeleton. Predicted to be involved in axonogenesis and cell motility. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]
RMEL3 (HGNC:53975): (enriched in melanoma 3)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.839
BS2
High AC in GnomAdExome4 at 18 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ACTBL2NM_001017992.4 linkuse as main transcriptc.533G>T p.Arg178Leu missense_variant 1/1 ENST00000423391.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ACTBL2ENST00000423391.3 linkuse as main transcriptc.533G>T p.Arg178Leu missense_variant 1/1 NM_001017992.4 P1
RMEL3ENST00000506106.1 linkuse as main transcriptn.120-11900C>A intron_variant, non_coding_transcript_variant 2

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
152086
Hom.:
0
Cov.:
32
show subpopulations
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:
0.00316
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000159
AC:
4
AN:
250932
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135576
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
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:
0.0000265
Gnomad OTH exome
AF:
0.000164
GnomAD4 exome
AF:
0.0000123
AC:
18
AN:
1461846
Hom.:
0
Cov.:
30
AF XY:
0.0000179
AC XY:
13
AN XY:
727214
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000162
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152206
Hom.:
0
Cov.:
32
AF XY:
0.0000403
AC XY:
3
AN XY:
74414
show subpopulations
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:
0.0000147
Gnomad4 OTH
AF:
0.00
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.000109
EpiControl
AF:
0.0000593

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsDec 14, 2022The c.533G>T (p.R178L) alteration is located in exon 1 (coding exon 1) of the ACTBL2 gene. This alteration results from a G to T substitution at nucleotide position 533, causing the arginine (R) at amino acid position 178 to be replaced by a leucine (L). 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
Pathogenic
0.80
BayesDel_addAF
Pathogenic
0.44
D
BayesDel_noAF
Pathogenic
0.46
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.71
D
Eigen
Pathogenic
0.81
Eigen_PC
Uncertain
0.63
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Benign
0.56
T
M_CAP
Benign
0.061
D
MetaRNN
Pathogenic
0.84
D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.6
H
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.69
T
PROVEAN
Pathogenic
-5.6
D
REVEL
Pathogenic
0.88
Sift4G
Pathogenic
0.0010
D
Polyphen
0.98
D
Vest4
0.64
MVP
0.68
MPC
0.23
ClinPred
0.99
D
GERP RS
4.8
Varity_R
0.88
gMVP
0.44

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

LitVar

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

Other links and lift over

dbSNP: rs200576412; hg19: chr5-56778002; API