12-5921308-C-A

Variant names:

• chr12-5921308-C-A
• rs182999590
• NM_001364791.2:c.266G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001364791.2(ANO2):​c.266G>T​(p.Arg89Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R89H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: ANO2 NM_001364791.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.21
• Publications: 0 publications found

Genes affected

ANO2 (HGNC:1183): (anoctamin 2) ANO2 belongs to a family of calcium-activated chloride channels (CaCCs) (reviewed by Hartzell et al., 2009 [PubMed 19015192]).[supplied by OMIM, Jan 2011]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18930122).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001364791.2. 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
	ANO2	NM_001364791.2	MANE Select	c.266G>T	p.Arg89Leu	missense	Exon 3 of 25	NP_001351720.1	A0A804HIY3
	ANO2	NM_001278596.3		c.266G>T	p.Arg89Leu	missense	Exon 3 of 27	NP_001265525.1	Q9NQ90-1
	ANO2	NM_001278597.3		c.254G>T	p.Arg85Leu	missense	Exon 3 of 27	NP_001265526.1	Q9NQ90-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANO2	ENST00000682330.1	MANE Select	c.266G>T	p.Arg89Leu	missense	Exon 3 of 25	ENSP00000507275.1	A0A804HIY3
	ANO2	ENST00000650848.1		c.266G>T	p.Arg89Leu	missense	Exon 3 of 27	ENSP00000498903.1	Q9NQ90-1
	ANO2	ENST00000356134.9	TSL:5	c.254G>T	p.Arg85Leu	missense	Exon 3 of 27	ENSP00000348453.5	Q9NQ90-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461694 Hom.: 0 Cov.: 34 AF XY: 0.00000550 AC XY: 4 AN XY: 727132

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111866

Other (OTH) AF: 0.0000166 AC: 1 AN: 60374

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.039	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.093	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.88	T
PhyloP100		1.2
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.25
Sift	Benign	0.30	T
Sift4G	Benign	0.21	T
Vest4		0.46
MutPred		0.56		Loss of MoRF binding (P = 0.0151)
MVP		0.24
MPC		0.11
ClinPred		0.41	T
GERP RS		4.2
gMVP		0.33
Mutation Taster		=89/11	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: rs182999590; hg19: chr12-6030474;