7-100643251-GGCACTTTCGCTCCAC-G

Variant names:

• chr7-100643251-GGCACTTTCGCTCCAC-G
• rs1562846694
• NM_016188.5:c.1261_1275delGTGGAGCGAAAGTGC

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM4 PP3 PP5_Moderate

The NM_016188.5(ACTL6B):​c.1261_1275delGTGGAGCGAAAGTGC​(p.Val421_Cys425del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACTL6B NM_016188.5 conservative_inframe_deletion
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.95
• Publications: 2 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: Uncertain_significance. The variant received 5 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_016188.5.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 7-100643251-GGCACTTTCGCTCCAC-G is Pathogenic according to our data. Variant chr7-100643251-GGCACTTTCGCTCCAC-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 599301.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1261_1275delGTGGAGCGAAAGTGC	p.Val421_Cys425del	conservative_inframe_deletion	Exon 14 of 14	NP_057272.1	O94805
	ACTL6B	NR_134539.2		n.1372_1386delGTGGAGCGAAAGTGC		non_coding_transcript_exon	Exon 14 of 14

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTL6B	ENST00000160382.10	TSL:1 MANE Select	c.1261_1275delGTGGAGCGAAAGTGC	p.Val421_Cys425del	conservative_inframe_deletion	Exon 14 of 14	ENSP00000160382.5	O94805
	ACTL6B	ENST00000970942.1		c.1330_1344delGTGGAGCGAAAGTGC	p.Val444_Cys448del	conservative_inframe_deletion	Exon 15 of 15	ENSP00000641001.1
	ACTL6B	ENST00000970941.1		c.1174_1188delGTGGAGCGAAAGTGC	p.Val392_Cys396del	conservative_inframe_deletion	Exon 13 of 13	ENSP00000641000.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.9
Mutation Taster		=54/146	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1562846694; hg19: chr7-100240874;