Variant 12-100223786-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_022496.5(ACTR6):c.1062C>A(p.Asn354Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000053 in 1,604,160 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000056 ( 0 hom. )

Consequence

ACTR6
NM_022496.5 missense, splice_region

Scores

Splicing: ADA: 0.4780

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.82

Variant links:

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]

ACTR6 links:

ACTR6 (HGNC:):

ACTR6 links:

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

DEPDC4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.783

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACTR6	NM_022496.5 linkuse as main transcript	c.1062C>A	p.Asn354Lys	missense_variant, splice_region_variant	11/11	ENST00000188312.7	NP_071941.1	Q9GZN1-1
ACTR6	NR_048568.2 linkuse as main transcript	n.1240C>A		splice_region_variant, non_coding_transcript_exon_variant	11/11
ACTR6	NR_048569.2 linkuse as main transcript	n.1112C>A		splice_region_variant, non_coding_transcript_exon_variant	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTR6	ENST00000188312.7 linkuse as main transcript	c.1062C>A	p.Asn354Lys	missense_variant, splice_region_variant	11/11	1	NM_022496.5	ENSP00000188312.2		Q9GZN1-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152072

Hom.:

Cov.:

show subpopulations

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000497

AC:

AN:

241278

Hom.:

AF XY:

0.0000460

AC XY:

AN XY:

130488

show subpopulations

Gnomad AFR exome

AF:

0.0000631

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000989

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000558

AC:

AN:

1452088

Hom.:

Cov.:

AF XY:

0.0000582

AC XY:

AN XY:

722134

show subpopulations

Gnomad4 AFR exome

AF:

0.0000608

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000712

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152072

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74268

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000378

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 13, 2022

The c.1062C>A (p.N354K) alteration is located in exon 11 (coding exon 11) of the ACTR6 gene. This alteration results from a C to A substitution at nucleotide position 1062, causing the asparagine (N) at amino acid position 354 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

0.0034

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.79

D;D;.;T

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.95

D;D;D;D

M_CAP

Uncertain

0.14

MetaRNN

Pathogenic

0.78

D;D;D;D

MetaSVM

Uncertain

0.35

MutationAssessor

Uncertain

2.3

M;.;.;.

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-4.0

D;D;D;D

REVEL

Benign

0.26

Sift

Uncertain

0.024

D;D;D;D

Sift4G

Uncertain

0.037

D;D;D;D

Polyphen

0.69

P;.;P;P

Vest4

0.77

MutPred

0.70

Gain of methylation at N354 (P = 0.0045);.;.;.;

MVP

0.97

MPC

1.4

ClinPred

0.55

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.61

gMVP

0.74

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.48

dbscSNV1_RF

Benign

0.54

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over