rs138168552

Variant names:

• chr11-26647815-C-T
• rs138168552
• NM_031418.4:c.2535C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BS1 BS2

The NM_031418.4(ANO3):​c.2535C>T​(p.Tyr845Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000143 in 1,613,238 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 Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00082 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000072 (0 hom.)
• Consequence: ANO3 NM_031418.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.828
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 11-26647815-C-T is Benign according to our data. Variant chr11-26647815-C-T is described in ClinVar as Benign. ClinVar VariationId is 241617.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.828 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000821 (125/152196) while in subpopulation AFR AF = 0.00286 (119/41544). AF 95% confidence interval is 0.00245. There are 0 homozygotes in GnomAd4. There are 51 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 125 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.2535C>T	p.Tyr845Tyr	synonymous	Exon 24 of 27	NP_113606.2	Q9BYT9-1
	ANO3	NM_001313726.2		c.2718C>T	p.Tyr906Tyr	synonymous	Exon 25 of 28	NP_001300655.1	A0A5F9ZHL6
	ANO3	NM_001313727.2		c.2097C>T	p.Tyr699Tyr	synonymous	Exon 21 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.2535C>T	p.Tyr845Tyr	synonymous	Exon 24 of 27	ENSP00000256737.3	Q9BYT9-1
	ANO3	ENST00000672621.1		c.2718C>T	p.Tyr906Tyr	synonymous	Exon 25 of 28	ENSP00000500506.1	A0A5F9ZHL6
	ANO3	ENST00000525139.5	TSL:5	c.2487C>T	p.Tyr829Tyr	synonymous	Exon 24 of 27	ENSP00000432576.1	E9PQ79

Frequencies

GnomAD3 genomes AF: 0.000822 AC: 125 AN: 152078 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00287

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

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: 0.0000147

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000171 AC: 43 AN: 251108 AF XY: 0.000147

Gnomad AFR exome AF: 0.00228

Gnomad AMR exome AF: 0.000174

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: 0.0000719 AC: 105 AN: 1461042 Hom.: 0 Cov.: 30 AF XY: 0.0000592 AC XY: 43 AN XY: 726804

African (AFR) AF: 0.00242 AC: 81 AN: 33470

American (AMR) AF: 0.000246 AC: 11 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39626

South Asian (SAS) AF: 0.00 AC: 0 AN: 86118

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111522

Other (OTH) AF: 0.000199 AC: 12 AN: 60356

GnomAD4 genome AF: 0.000821 AC: 125 AN: 152196 Hom.: 0 Cov.: 32 AF XY: 0.000685 AC XY: 51 AN XY: 74410

African (AFR) AF: 0.00286 AC: 119 AN: 41544

American (AMR) AF: 0.000196 AC: 3 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67992

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.000461 Hom.: 0

Bravo AF: 0.000975

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Dystonic disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	6.3
DANN	Benign	0.47
PhyloP100		0.83
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs138168552; hg19: chr11-26669362;