11-26332285-C-G

Variant names:

• chr11-26332285-C-G
• rs750220809
• NM_031418.4:c.10C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_031418.4(ANO3):​c.10C>G​(p.His4Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ANO3 NM_031418.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.66

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANO3	NM_031418.4	c.10C>G	p.His4Asp	missense_variant	Exon 1 of 27	ENST00000256737.8	NP_113606.2
ANO3	XM_047427399.1	c.10C>G	p.His4Asp	missense_variant	Exon 1 of 26		XP_047283355.1
ANO3	NM_001313726.2	c.229+22566C>G		intron_variant	Intron 2 of 27		NP_001300655.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANO3	ENST00000256737.8	c.10C>G	p.His4Asp	missense_variant	Exon 1 of 27	1	NM_031418.4	ENSP00000256737.3
ANO3	ENST00000531646.1	c.10C>G	p.His4Asp	missense_variant	Exon 1 of 5	4		ENSP00000435275.1
ANO3	ENST00000672621.1	c.229+22566C>G		intron_variant	Intron 2 of 27			ENSP00000500506.1
ANO3	ENST00000525139.5	c.-3+22566C>G		intron_variant	Intron 1 of 26	5		ENSP00000432576.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251486 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135914

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461882 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.075	T;T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.72	T;T
M_CAP	Benign	0.033	D
MetaRNN	Uncertain	0.46	T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	0.81	L;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	0.030	N;N
REVEL	Benign	0.24
Sift	Benign	0.050	D;D
Sift4G	Benign	0.14	T;T
Polyphen		0.93	P;.
Vest4		0.64
MutPred		0.24		Gain of catalytic residue at H4 (P = 0.0126);Gain of catalytic residue at H4 (P = 0.0126);
MVP		0.66
MPC		0.32
ClinPred		0.83	D
GERP RS		5.9
Varity_R		0.35
gMVP		0.63

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

Publications

LitVar

Other links and lift over

dbSNP: rs750220809; hg19: chr11-26353832;