12-100220079-C-G

Variant names:

• chr12-100220079-C-G
• rs749116716
• NM_022496.5:c.994C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_022496.5(ACTR6):​c.994C>G​(p.Arg332Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R332W) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACTR6 NM_022496.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.59
• Publications: 1 publications found

Genes affected

ACTR6 (HGNC:24025): (actin related protein 6) Predicted to enable nucleosome binding activity. Predicted to be involved in histone exchange. Predicted to be located in nucleus. Predicted to be part of Swr1 complex. [provided by Alliance of Genome Resources, Apr 2022]

DEPDC4 (HGNC:22952): (DEP domain containing 4) Predicted to be involved in intracellular signal transduction. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.945

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022496.5. 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
	ACTR6	NM_022496.5	MANE Select	c.994C>G	p.Arg332Gly	missense	Exon 10 of 11	NP_071941.1	Q9GZN1-1
	ACTR6	NR_048568.2		n.1172C>G		non_coding_transcript_exon	Exon 10 of 11
	ACTR6	NR_048569.2		n.1044C>G		non_coding_transcript_exon	Exon 10 of 11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTR6	ENST00000188312.7	TSL:1 MANE Select	c.994C>G	p.Arg332Gly	missense	Exon 10 of 11	ENSP00000188312.2	Q9GZN1-1
	ACTR6	ENST00000553038.5	TSL:1	n.*474C>G		non_coding_transcript_exon	Exon 9 of 10	ENSP00000447641.1	F8W043
	ACTR6	ENST00000553038.5	TSL:1	n.*474C>G		3_prime_UTR	Exon 9 of 10	ENSP00000447641.1	F8W043

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Pathogenic	0.68
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		5.6
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-6.9	D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.014	D
Polyphen		0.99	D
Vest4		0.98
MutPred		0.66		Loss of phosphorylation at S335 (P = 0.074)
MVP		0.98
MPC		0.99
ClinPred		1.0	D
GERP RS		4.1
Varity_R		0.93
gMVP		0.96
Mutation Taster		=21/79	disease causing

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

Other links and lift over

dbSNP: rs749116716; hg19: chr12-100613857;