chr11-26525644-C-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_031418.4(ANO3):c.702C>G(p.Cys234Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,066 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

ANO3
NM_031418.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.745

Publications

3 publications found

Variant links:

Genes affected

ANO3 (HGNC:14004): (anoctamin 3) The protein encoded by this gene belongs to the TMEM16 family of predicted membrane proteins, that are also known as anoctamins. While little is known about the function of this gene, mutations in this gene have been associated with some cases of autosomal dominant craniocervical dystonia. Cells from individuals with a mutation in this gene exhibited abnormalities in endoplasmic reticulum-dependent calcium signaling. Studies in rat show that the rat ortholog of this protein interacts with, and modulates the activity of a sodium-activated potassium channel. Deletion of this gene caused increased pain sensitivity in the rat model system. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Aug 2015]

ANO3 Gene-Disease associations (from GenCC):

dystonia 24
Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, G2P

ANO3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANO3	NM_031418.4 link	c.702C>G	p.Cys234Trp	missense_variant	Exon 7 of 27	ENST00000256737.8	NP_113606.2	Q9BYT9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ANO3	ENST00000256737.8 link	c.702C>G	p.Cys234Trp	missense_variant	Exon 7 of 27	1	NM_031418.4	ENSP00000256737.3	Q9BYT9-1
ANO3	ENST00000672621.1 link	c.885C>G	p.Cys295Trp	missense_variant	Exon 8 of 28			ENSP00000500506.1	A0A5F9ZHL6
ANO3	ENST00000525139.5 link	c.654C>G	p.Cys218Trp	missense_variant	Exon 7 of 27	5		ENSP00000432576.1	E9PQ79
ANO3	ENST00000531568.1 link	c.264C>G	p.Cys88Trp	missense_variant	Exon 4 of 24	2		ENSP00000432394.1	Q9BYT9-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1458066

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725264

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33274

American (AMR)

AF:

0.00

AC:

AN:

44202

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26052

East Asian (EAS)

AF:

0.00

AC:

AN:

39448

South Asian (SAS)

AF:

0.00

AC:

AN:

85490

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53364

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

9.01e-7

AC:

AN:

1110238

Other (OTH)

AF:

0.00

AC:

AN:

60244

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Aug 23, 2016

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The C234W variant in the ANO3 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The C234W variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The C234W variant is anon-conservative amino acid substitution, which occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.56

BayesDel_addAF

Benign

-0.025

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.087

T;T;.

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.16

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.93

D;D;D

M_CAP

Uncertain

0.093

MetaRNN

Uncertain

0.57

D;D;D

MetaSVM

Benign

-0.92

MutationAssessor

Uncertain

2.2

.;M;.

PhyloP100

0.74

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.8

N;N;N

REVEL

Benign

0.18

Sift

Uncertain

0.017

D;D;D

Sift4G

Benign

0.18

T;T;T

Polyphen

0.66

.;P;.

Vest4

0.67

MutPred

0.37

.;Loss of methylation at K233 (P = 0.023);.;

MVP

0.53

MPC

0.74

ClinPred

0.83

GERP RS

1.2

Varity_R

0.17

gMVP

0.63

Mutation Taster

=46/54

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over