chr12-100210112-C-T

Variant names:

• chr12-100210112-C-T
• rs142634632
• NM_022496.5:c.419C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_022496.5(ACTR6):​c.419C>T​(p.Pro140Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000236 in 1,608,898 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: ACTR6 NM_022496.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.38
• Publications: 3 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.812

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.419C>T	p.Pro140Leu	missense	Exon 5 of 11	NP_071941.1	Q9GZN1-1
	ACTR6	NR_048568.2		n.597C>T		non_coding_transcript_exon	Exon 5 of 11
	ACTR6	NR_048569.2		n.469C>T		non_coding_transcript_exon	Exon 5 of 11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTR6	ENST00000188312.7	TSL:1 MANE Select	c.419C>T	p.Pro140Leu	missense	Exon 5 of 11	ENSP00000188312.2	Q9GZN1-1
	ACTR6	ENST00000553038.5	TSL:1	n.380-183C>T		intron	N/A	ENSP00000447641.1	F8W043
	ACTR6	ENST00000926809.1		c.413C>T	p.Pro138Leu	missense	Exon 5 of 11	ENSP00000596868.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151918 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.0000161 AC: 4 AN: 248078 AF XY: 0.0000149

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000355

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000254 AC: 37 AN: 1456980 Hom.: 0 Cov.: 30 AF XY: 0.0000262 AC XY: 19 AN XY: 724558

African (AFR) AF: 0.00 AC: 0 AN: 33198

American (AMR) AF: 0.00 AC: 0 AN: 43970

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26028

East Asian (EAS) AF: 0.00 AC: 0 AN: 39552

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 84978

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53314

Middle Eastern (MID) AF: 0.000197 AC: 1 AN: 5088

European-Non Finnish (NFE) AF: 0.0000297 AC: 33 AN: 1110682

Other (OTH) AF: 0.0000332 AC: 2 AN: 60170

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151918 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74162

African (AFR) AF: 0.00 AC: 0 AN: 41340

American (AMR) AF: 0.00 AC: 0 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10528

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000594

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.63	D
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.082	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Benign	1.4	L
PhyloP100		4.4
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.082	T
Polyphen		0.26	B
Vest4		0.49
MVP		0.96
MPC		1.0
ClinPred		0.88	D
GERP RS		5.2
Varity_R		0.22
gMVP		0.67
Mutation Taster		=63/37	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs142634632; hg19: chr12-100603890; COSMIC: COSV51843310; COSMIC: COSV51843310;