rs146532706

Variant names:

• chr11-26525656-C-T
• rs146532706
• NM_031418.4:c.714C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-26525656-C-T
• chr11-26525656-C-A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_031418.4(ANO3):​c.714C>T​(p.Asp238Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00049 in 1,609,678 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (1 hom.)
• Consequence: ANO3 NM_031418.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.22
• Publications: 0 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

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 11-26525656-C-T is Benign according to our data. Variant chr11-26525656-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 412870.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.22 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00269 (408/151850) while in subpopulation AFR AF = 0.0092 (381/41424). AF 95% confidence interval is 0.00844. There are 1 homozygotes in GnomAd4. There are 191 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 408 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.714C>T	p.Asp238Asp	synonymous	Exon 7 of 27	NP_113606.2	Q9BYT9-1
	ANO3	NM_001313726.2		c.897C>T	p.Asp299Asp	synonymous	Exon 8 of 28	NP_001300655.1	A0A5F9ZHL6
	ANO3	NM_001313727.2		c.276C>T	p.Asp92Asp	synonymous	Exon 4 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.714C>T	p.Asp238Asp	synonymous	Exon 7 of 27	ENSP00000256737.3	Q9BYT9-1
	ANO3	ENST00000672621.1		c.897C>T	p.Asp299Asp	synonymous	Exon 8 of 28	ENSP00000500506.1	A0A5F9ZHL6
	ANO3	ENST00000525139.5	TSL:5	c.666C>T	p.Asp222Asp	synonymous	Exon 7 of 27	ENSP00000432576.1	E9PQ79

Frequencies

GnomAD3 genomes AF: 0.00262 AC: 397 AN: 151732 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00896

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00112

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: 0.0000589

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.000594 AC: 147 AN: 247526 AF XY: 0.000448

Gnomad AFR exome AF: 0.00799

Gnomad AMR exome AF: 0.000358

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.0000356

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000261 AC: 380 AN: 1457828 Hom.: 1 Cov.: 29 AF XY: 0.000230 AC XY: 167 AN XY: 725136

African (AFR) AF: 0.00794 AC: 264 AN: 33240

American (AMR) AF: 0.000476 AC: 21 AN: 44164

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26052

East Asian (EAS) AF: 0.00 AC: 0 AN: 39446

South Asian (SAS) AF: 0.0000468 AC: 4 AN: 85410

European-Finnish (FIN) AF: 0.000112 AC: 6 AN: 53354

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5758

European-Non Finnish (NFE) AF: 0.0000432 AC: 48 AN: 1110210

Other (OTH) AF: 0.000598 AC: 36 AN: 60194

GnomAD4 genome AF: 0.00269 AC: 408 AN: 151850 Hom.: 1 Cov.: 32 AF XY: 0.00257 AC XY: 191 AN XY: 74212

African (AFR) AF: 0.00920 AC: 381 AN: 41424

American (AMR) AF: 0.00112 AC: 17 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10524

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000589 AC: 4 AN: 67914

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00124 Hom.: 0

Bravo AF: 0.00276

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	ANO3-related disorder (1)
-	-	1	Dystonia 24 (1)
-	-	1	Dystonic disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	8.9
DANN	Benign	0.49
PhyloP100		2.2
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs146532706; hg19: chr11-26547203;