rs1485296559

Variant names:

• chr7-100646265-G-C
• rs1485296559
• NM_016188.5:c.1184C>G

Your query was ambiguous. Multiple possible variants found:

• chr7-100646265-G-C
• chr7-100646265-G-A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Strong

The NM_016188.5(ACTL6B):​c.1184C>G​(p.Ser395Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACTL6B NM_016188.5 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 9.60
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 76

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• intellectual developmental disorder with severe speech and ambulation defects

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the ACTL6B gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 18 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 3.2738 (above the threshold of 3.09). Trascript score misZ: 3.3665 (above the threshold of 3.09). GenCC associations: The gene is linked to intellectual developmental disorder with severe speech and ambulation defects, developmental and epileptic encephalopathy, 76, undetermined early-onset epileptic encephalopathy, syndromic intellectual disability.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016188.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTL6B	NM_016188.5	MANE Select	c.1184C>G	p.Ser395Cys	missense	Exon 13 of 14	NP_057272.1	O94805
	ACTL6B	NR_134539.2		n.1295C>G		non_coding_transcript_exon	Exon 13 of 14

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTL6B	ENST00000160382.10	TSL:1 MANE Select	c.1184C>G	p.Ser395Cys	missense	Exon 13 of 14	ENSP00000160382.5	O94805
	ACTL6B	ENST00000970942.1		c.1253C>G	p.Ser418Cys	missense	Exon 14 of 15	ENSP00000641001.1
	ACTL6B	ENST00000863236.1		c.917C>G	p.Ser306Cys	missense	Exon 11 of 12	ENSP00000533295.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	ACTL6B-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.96	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		9.6
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.91		Loss of disorder (P = 0.0702)
MVP		0.97
MPC		2.3
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.62
gMVP		0.87
Mutation Taster		=21/79	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1485296559; hg19: chr7-100243888;