chr11-26525646-A-G

Variant names:

• chr11-26525646-A-G
• rs144792604
• NM_031418.4:c.704A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_031418.4(ANO3):​c.704A>G​(p.Tyr235Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000338 in 1,610,924 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00036 (0 hom.)
• Consequence: ANO3 NM_031418.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 6.42
• Publications: 9 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 -9 ACMG points.

• BP6: Variant 11-26525646-A-G is Benign according to our data. Variant chr11-26525646-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 388790.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.00036 (525/1458882) while in subpopulation NFE AF = 0.000443 (492/1110676). AF 95% confidence interval is 0.000411. There are 0 homozygotes in GnomAdExome4. There are 271 alleles in the male GnomAdExome4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High AC in GnomAd4 at 20 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.704A>G	p.Tyr235Cys	missense	Exon 7 of 27	NP_113606.2	Q9BYT9-1
	ANO3	NM_001313726.2		c.887A>G	p.Tyr296Cys	missense	Exon 8 of 28	NP_001300655.1	A0A5F9ZHL6
	ANO3	NM_001313727.2		c.266A>G	p.Tyr89Cys	missense	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.704A>G	p.Tyr235Cys	missense	Exon 7 of 27	ENSP00000256737.3	Q9BYT9-1
	ANO3	ENST00000672621.1		c.887A>G	p.Tyr296Cys	missense	Exon 8 of 28	ENSP00000500506.1	A0A5F9ZHL6
	ANO3	ENST00000525139.5	TSL:5	c.656A>G	p.Tyr219Cys	missense	Exon 7 of 27	ENSP00000432576.1	E9PQ79

Frequencies

GnomAD3 genomes AF: 0.000132 AC: 20 AN: 152042 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000265

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000262 AC: 65 AN: 248376 AF XY: 0.000290

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000890

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000497

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000360 AC: 525 AN: 1458882 Hom.: 0 Cov.: 29 AF XY: 0.000373 AC XY: 271 AN XY: 725680

African (AFR) AF: 0.0000900 AC: 3 AN: 33316

American (AMR) AF: 0.0000677 AC: 3 AN: 44312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26064

East Asian (EAS) AF: 0.00 AC: 0 AN: 39510

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85626

European-Finnish (FIN) AF: 0.000225 AC: 12 AN: 53358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.000443 AC: 492 AN: 1110676

Other (OTH) AF: 0.000232 AC: 14 AN: 60262

GnomAD4 genome AF: 0.000132 AC: 20 AN: 152042 Hom.: 0 Cov.: 32 AF XY: 0.0000943 AC XY: 7 AN XY: 74258

African (AFR) AF: 0.0000483 AC: 2 AN: 41428

American (AMR) AF: 0.00 AC: 0 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 67974

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000368 Hom.: 0

Bravo AF: 0.000174

EpiCase AF: 0.000383

EpiControl AF: 0.000358

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
PhyloP100		6.4
Varity_R		0.24
gMVP		0.60
Mutation Taster		=71/29	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs144792604; hg19: chr11-26547193;