chr11-26634298-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_031418.4(ANO3):​c.1968C>T​(p.Ile656Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00788 in 1,611,710 control chromosomes in the GnomAD database, including 90 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. I656I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0057 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0081 (86 hom.)
• Consequence: ANO3 NM_031418.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 11-26634298-C-T is Benign according to our data. Variant chr11-26634298-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 241616.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.422 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00575 (875/152186) while in subpopulation NFE AF = 0.00768 (522/68004). AF 95% confidence interval is 0.00713. There are 4 homozygotes in GnomAd4. There are 455 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 875 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>T	p.Ile656Ile	synonymous	Exon 19 of 27	NP_113606.2	Q9BYT9-1
	ANO3	NM_001313726.2		c.2151C>T	p.Ile717Ile	synonymous	Exon 20 of 28	NP_001300655.1	A0A5F9ZHL6
	ANO3	NM_001313727.2		c.1530C>T	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>T	p.Ile656Ile	synonymous	Exon 19 of 27	ENSP00000256737.3	Q9BYT9-1
	ANO3	ENST00000672621.1		c.2151C>T	p.Ile717Ile	synonymous	Exon 20 of 28	ENSP00000500506.1	A0A5F9ZHL6
	ANO3	ENST00000525139.5	TSL:5	c.1920C>T	p.Ile640Ile	synonymous	Exon 19 of 27	ENSP00000432576.1	E9PQ79

Frequencies

GnomAD3 genomes AF: 0.00575 AC: 875 AN: 152068 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.00879

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.0225

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00768

Gnomad OTH AF: 0.00670

GnomAD2 exomes AF: 0.00632 AC: 1585 AN: 250898 AF XY: 0.00644

Gnomad AFR exome AF: 0.00160

Gnomad AMR exome AF: 0.00261

Gnomad ASJ exome AF: 0.000497

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0233

Gnomad NFE exome AF: 0.00783

Gnomad OTH exome AF: 0.00736

GnomAD4 exome AF: 0.00810 AC: 11822 AN: 1459524 Hom.: 86 Cov.: 29 AF XY: 0.00780 AC XY: 5664 AN XY: 726228

African (AFR) AF: 0.00144 AC: 48 AN: 33424

American (AMR) AF: 0.00235 AC: 105 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.000192 AC: 5 AN: 26098

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

South Asian (SAS) AF: 0.000812 AC: 70 AN: 86172

European-Finnish (FIN) AF: 0.0223 AC: 1190 AN: 53376

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5764

European-Non Finnish (NFE) AF: 0.00890 AC: 9885 AN: 1110058

Other (OTH) AF: 0.00849 AC: 512 AN: 60290

GnomAD4 genome AF: 0.00575 AC: 875 AN: 152186 Hom.: 4 Cov.: 32 AF XY: 0.00611 AC XY: 455 AN XY: 74408

African (AFR) AF: 0.00113 AC: 47 AN: 41538

American (AMR) AF: 0.00216 AC: 33 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3466

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5166

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4822

European-Finnish (FIN) AF: 0.0225 AC: 238 AN: 10594

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

European-Non Finnish (NFE) AF: 0.00768 AC: 522 AN: 68004

Other (OTH) AF: 0.00664 AC: 14 AN: 2110

Alfa AF: 0.00542 Hom.: 1

Bravo AF: 0.00434

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Dystonia 24 (3)
-	-	2	not provided (2)
-	-	1	Dystonic disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	0.63
DANN	Benign	0.69
PhyloP100		-0.42
Mutation Taster		=94/6	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: rs149050831; hg19: chr11-26655845; COSMIC: COSV56792796;