rs149050831

Variant names:

• chr11-26634298-C-A
• rs149050831
• NM_031418.4:c.1968C>A

Your query was ambiguous. Multiple possible variants found:

• chr11-26634298-C-A
• chr11-26634298-C-T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS2

The NM_031418.4(ANO3):​c.1968C>A​(p.Ile656Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000048 in 1,459,682 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. I656I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: ANO3 NM_031418.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.422
• Publications: 4 publications found

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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P, Orphanet

ENSG00000300991 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 11-26634298-C-A is Benign according to our data. Variant chr11-26634298-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 444247.
• BP7: Synonymous conserved (PhyloP=-0.422 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031418.4. 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
	ANO3	NM_031418.4	MANE Select	c.1968C>A	p.Ile656Ile	synonymous	Exon 19 of 27	NP_113606.2	Q9BYT9-1
	ANO3	NM_001313726.2		c.2151C>A	p.Ile717Ile	synonymous	Exon 20 of 28	NP_001300655.1	A0A5F9ZHL6
	ANO3	NM_001313727.2		c.1530C>A	p.Ile510Ile	synonymous	Exon 16 of 24	NP_001300656.1	Q9BYT9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANO3	ENST00000256737.8	TSL:1 MANE Select	c.1968C>A	p.Ile656Ile	synonymous	Exon 19 of 27	ENSP00000256737.3	Q9BYT9-1
	ANO3	ENST00000672621.1		c.2151C>A	p.Ile717Ile	synonymous	Exon 20 of 28	ENSP00000500506.1	A0A5F9ZHL6
	ANO3	ENST00000525139.5	TSL:5	c.1920C>A	p.Ile640Ile	synonymous	Exon 19 of 27	ENSP00000432576.1	E9PQ79

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250898 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000870

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000480 AC: 7 AN: 1459682 Hom.: 0 Cov.: 29 AF XY: 0.00000688 AC XY: 5 AN XY: 726304

African (AFR) AF: 0.00 AC: 0 AN: 33424

American (AMR) AF: 0.0000671 AC: 3 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39652

South Asian (SAS) AF: 0.00 AC: 0 AN: 86174

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5764

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1110194

Other (OTH) AF: 0.0000166 AC: 1 AN: 60300

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 1

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Dystonic disorder (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	0.15
DANN	Benign	0.66
PhyloP100		-0.42
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs149050831; hg19: chr11-26655845;