Variant 5-57481654-T-C details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_001017992.4(ACTBL2):c.1054A>G(p.Thr352Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000735 in 1,614,118 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00086 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00072 ( 3 hom. )

Consequence

ACTBL2
NM_001017992.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.96

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]

ACTBL2 links:

RMEL3 (HGNC:53975): (enriched in melanoma 3)

RMEL3 links:

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=0.10929403).

BS2

High AC in GnomAd4 at 131 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTBL2	NM_001017992.4 linkuse as main transcript	c.1054A>G	p.Thr352Ala	missense_variant	1/1	ENST00000423391.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTBL2	ENST00000423391.3 linkuse as main transcript	c.1054A>G	p.Thr352Ala	missense_variant	1/1		NM_001017992.4	P1
RMEL3	ENST00000506106.1 linkuse as main transcript	n.120-12421T>C		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes

AF:

0.000861

AC:

131

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00154

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000916

AC:

230

AN:

251178

Hom.:

AF XY:

0.000906

AC XY:

123

AN XY:

135740

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00166

Gnomad NFE exome

AF:

0.00166

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000722

AC:

1056

AN:

1461830

Hom.:

Cov.:

AF XY:

0.000741

AC XY:

539

AN XY:

727202

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00170

Gnomad4 NFE exome

AF:

0.000844

Gnomad4 OTH exome

AF:

0.000315

GnomAD4 genome

AF:

0.000860

AC:

131

AN:

152288

Hom.:

Cov.:

AF XY:

0.000833

AC XY:

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00188

Gnomad4 NFE

AF:

0.00154

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00100

Hom.:

Bravo

AF:

0.000525

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.00114

AC:

138

EpiCase

AF:

0.000981

EpiControl

AF:

0.000474

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 submitter

clinical testing

Ambry Genetics

Aug 16, 2021

The c.1054A>G (p.T352A) alteration is located in exon 1 (coding exon 1) of the ACTBL2 gene. This alteration results from a A to G substitution at nucleotide position 1054, causing the threonine (T) at amino acid position 352 to be replaced by an alanine (A). 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

Uncertain

0.42

BayesDel_addAF

Benign

-0.022

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.55

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.92

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.11

MetaSVM

Uncertain

0.66

MutationAssessor

Uncertain

2.6

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-2.5

REVEL

Pathogenic

0.90

Sift4G

Uncertain

0.039

Polyphen

0.091

Vest4

0.80

MVP

0.68

MPC

0.12

ClinPred

0.14

GERP RS

5.0

Varity_R

0.71

gMVP

0.23

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over