rs1060499738

Positions:

chr7-100647014-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PP2PP3_StrongPP5_Moderate

The NM_016188.5(ACTL6B):c.893G>A(p.Arg298Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,934 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 Likely pathogenic (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

ACTL6B
NM_016188.5 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:3

Conservation

PhyloP100: 7.57

Variant links:

Genes affected

ACTL6B (HGNC:160): (actin like 6B) The protein encoded by this gene is a member of a family of actin-related proteins (ARPs) which share significant amino acid sequence identity to conventional actins. Both actins and ARPs have an actin fold, which is an ATP-binding cleft, as a common feature. The ARPs are involved in diverse cellular processes, including vesicular transport, spindle orientation, nuclear migration and chromatin remodeling. This gene encodes a subunit of the BAF (BRG1/brm-associated factor) complex in mammals, which is functionally related to SWI/SNF complex in S. cerevisiae and Drosophila; the latter is thought to facilitate transcriptional activation of specific genes by antagonizing chromatin-mediated transcriptional repression. This subunit may be involved in the regulation of genes by structural modulation of their chromatin, specifically in the brain. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]

ACTL6B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ACTL6B. . Gene score misZ 3.2738 (greater than the threshold 3.09). Trascript score misZ 3.3665 (greater than threshold 3.09). GenCC has associacion of gene with intellectual developmental disorder with severe speech and ambulation defects, syndromic intellectual disability, developmental and epileptic encephalopathy, 76, undetermined early-onset epileptic encephalopathy.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.988

PP5

Variant 7-100647014-C-T is Pathogenic according to our data. Variant chr7-100647014-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 402140.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-100647014-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTL6B	NM_016188.5 linkuse as main transcript	c.893G>A	p.Arg298Gln	missense_variant	10/14	ENST00000160382.10
ACTL6B	NR_134539.2 linkuse as main transcript	n.987G>A		non_coding_transcript_exon_variant	10/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTL6B	ENST00000160382.10 linkuse as main transcript	c.893G>A	p.Arg298Gln	missense_variant	10/14	1	NM_016188.5	P1
ACTL6B	ENST00000487125.1 linkuse as main transcript	n.455G>A		non_coding_transcript_exon_variant	3/7	5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152096

Hom.:

Cov.:

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:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461838

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152096

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74284

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

Bravo

AF:

0.0000113

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 76

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 25, 2020	- -
Likely pathogenic, no assertion criteria provided	research	Houlden Lab, UCL Institute of Neurology	-	- -

Global developmental delay;C3714756:Intellectual disability

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

ACTL6B is a component of brain-specific chromatin remodeling complexes containing the ATPases Brg1 (SMARCA4) and Brm (SMARCA2). Several SMARCA genes are konown to be associated with DD/ID syndromes -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.95

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.94

M_CAP

Uncertain

0.19

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.8

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-3.7

REVEL

Pathogenic

0.88

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0050

Polyphen

0.99

Vest4

0.97

MutPred

0.96

Loss of sheet (P = 0.0817);

MVP

0.99

MPC

2.5

ClinPred

0.99

GERP RS

6.0

Varity_R

0.46

gMVP

0.97

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