rs117748217

Variant names:

• chr11-26660309-C-T
• rs117748217
• NM_031418.4:c.2811C>T

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.2811C>T​(p.Asp937Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00945 in 1,613,220 control chromosomes in the GnomAD database, including 122 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0075 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0096 (111 hom.)
• Consequence: ANO3 NM_031418.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.861
• 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.27).
• BP6: Variant 11-26660309-C-T is Benign according to our data. Variant chr11-26660309-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 412868.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.861 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00754 (1148/152220) while in subpopulation AMR AF = 0.014 (214/15260). AF 95% confidence interval is 0.0125. There are 11 homozygotes in GnomAd4. There are 525 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1148 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.2811C>T	p.Asp937Asp	synonymous	Exon 27 of 27	NP_113606.2	Q9BYT9-1
	ANO3	NM_001313726.2		c.2994C>T	p.Asp998Asp	synonymous	Exon 28 of 28	NP_001300655.1	A0A5F9ZHL6
	ANO3	NM_001313727.2		c.2373C>T	p.Asp791Asp	synonymous	Exon 24 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.2811C>T	p.Asp937Asp	synonymous	Exon 27 of 27	ENSP00000256737.3	Q9BYT9-1
	ANO3	ENST00000672621.1		c.2994C>T	p.Asp998Asp	synonymous	Exon 28 of 28	ENSP00000500506.1	A0A5F9ZHL6
	ANO3	ENST00000525139.5	TSL:5	c.2763C>T	p.Asp921Asp	synonymous	Exon 27 of 27	ENSP00000432576.1	E9PQ79

Frequencies

GnomAD3 genomes AF: 0.00754 AC: 1147 AN: 152102 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00220

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0140

Gnomad ASJ AF: 0.0380

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00745

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00906

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.00873 AC: 2189 AN: 250776 AF XY: 0.00913

Gnomad AFR exome AF: 0.00166

Gnomad AMR exome AF: 0.0111

Gnomad ASJ exome AF: 0.0324

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.000785

Gnomad NFE exome AF: 0.0101

Gnomad OTH exome AF: 0.0142

GnomAD4 exome AF: 0.00965 AC: 14097 AN: 1461000 Hom.: 111 Cov.: 31 AF XY: 0.00966 AC XY: 7020 AN XY: 726792

African (AFR) AF: 0.00236 AC: 79 AN: 33420

American (AMR) AF: 0.0118 AC: 529 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.0340 AC: 887 AN: 26110

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39676

South Asian (SAS) AF: 0.00634 AC: 546 AN: 86074

European-Finnish (FIN) AF: 0.00137 AC: 73 AN: 53416

Middle Eastern (MID) AF: 0.0375 AC: 216 AN: 5758

European-Non Finnish (NFE) AF: 0.00993 AC: 11040 AN: 1111534

Other (OTH) AF: 0.0120 AC: 722 AN: 60366

GnomAD4 genome AF: 0.00754 AC: 1148 AN: 152220 Hom.: 11 Cov.: 32 AF XY: 0.00705 AC XY: 525 AN XY: 74416

African (AFR) AF: 0.00221 AC: 92 AN: 41548

American (AMR) AF: 0.0140 AC: 214 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.0380 AC: 132 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5170

South Asian (SAS) AF: 0.00725 AC: 35 AN: 4830

European-Finnish (FIN) AF: 0.00141 AC: 15 AN: 10608

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00907 AC: 617 AN: 68010

Other (OTH) AF: 0.0104 AC: 22 AN: 2116

Alfa AF: 0.0101 Hom.: 6

Bravo AF: 0.00879

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.0123

EpiControl AF: 0.0144

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Dystonia 24 (1)
-	-	1	Dystonic disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	11
DANN	Benign	0.61
PhyloP100		0.86
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs117748217; hg19: chr11-26681856; COSMIC: COSV56792910;