7-5528465-CC-TT

Variant names:

• chr7-5528465-CC-TT
• NM_001101.5:c.617_618delGGinsAA
• ACTB p.Arg206Gln

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS1_Very_Strong PM1 PM5 PP2 PP3

The NM_001101.5(ACTB):​c.617_618delGGinsAA​(p.Arg206Gln) variant causes a missense 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 MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R206W) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ACTB NM_001101.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.62
• Publications: 0 publications found

Genes affected

ACTB (HGNC:132): (actin beta) This gene encodes one of six different actin proteins. Actins are highly conserved proteins that are involved in cell motility, structure, integrity, and intercellular signaling. The encoded protein is a major constituent of the contractile apparatus and one of the two nonmuscle cytoskeletal actins that are ubiquitously expressed. Mutations in this gene cause Baraitser-Winter syndrome 1, which is characterized by intellectual disability with a distinctive facial appearance in human patients. Numerous pseudogenes of this gene have been identified throughout the human genome. [provided by RefSeq, Aug 2017]

ACTB Gene-Disease associations (from GenCC):

• Baraitser-Winter cerebrofrontofacial syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Baraitser-Winter syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• developmental malformations-deafness-dystonia syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Illumina, Genomics England PanelApp
• ACTB-associated syndromic thrombocytopenia

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics, ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PS1: Transcript NM_001101.5 (ACTB) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_001101.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-5528467-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 860924.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the ACTB gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 94 curated pathogenic missense variants (we use a threshold of 10). The gene has 13 curated benign missense variants. Trascript score misZ: 7.6852 (above the threshold of 3.09). GenCC associations: The gene is linked to developmental malformations-deafness-dystonia syndrome, Baraitser-Winter syndrome 1, Baraitser-Winter cerebrofrontofacial syndrome, ACTB-associated syndromic thrombocytopenia.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001101.5. 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
	ACTB	NM_001101.5	MANE Select	c.617_618delGGinsAA	p.Arg206Gln	missense	N/A	NP_001092.1	P60709

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTB	ENST00000646664.1	MANE Select	c.617_618delGGinsAA	p.Arg206Gln	missense	N/A	ENSP00000494750.1	P60709
	ACTB	ENST00000425660.5	TSL:1	n.*280_*281delGGinsAA		non_coding_transcript_exon	Exon 5 of 7	ENSP00000409264.1	G5E9R0
	ACTB	ENST00000425660.5	TSL:1	n.*280_*281delGGinsAA		3_prime_UTR	Exon 5 of 7	ENSP00000409264.1	G5E9R0

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.6

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr7-5568096;