chr11-26525644-C-G

Variant names:

• chr11-26525644-C-G
• rs886037882
• NM_031418.4:c.702C>G

Variant summary

Our verdict is Uncertain significance. Variant got 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.745

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 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	c.702C>G	p.Cys234Trp	missense_variant	Exon 7 of 27	ENST00000256737.8	NP_113606.2

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458066 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 725264

Gnomad4 AFR exome AF: 0.00

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: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.087	T;T;.
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Uncertain	0.093	D
MetaRNN	Uncertain	0.57	D;D;D
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.2	.;M;.
PrimateAI	Benign	0.41	T
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	D
GERP RS		1.2
Varity_R		0.17
gMVP		0.63

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

LitVar

Other links and lift over

dbSNP: rs886037882; hg19: chr11-26547191;