12-5921308-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001364791.2(ANO2):​c.266G>A​(p.Arg89His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000667 in 1,613,916 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0025 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00047 (2 hom.)
• Consequence: ANO2 NM_001364791.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.21
• Publications: 5 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0059717596).
• BP6: Variant 12-5921308-C-T is Benign according to our data. Variant chr12-5921308-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2642600.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

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>A	p.Arg89His	missense	Exon 3 of 25	NP_001351720.1	A0A804HIY3
	ANO2	NM_001278596.3		c.266G>A	p.Arg89His	missense	Exon 3 of 27	NP_001265525.1	Q9NQ90-1
	ANO2	NM_001278597.3		c.254G>A	p.Arg85His	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>A	p.Arg89His	missense	Exon 3 of 25	ENSP00000507275.1	A0A804HIY3
	ANO2	ENST00000650848.1		c.266G>A	p.Arg89His	missense	Exon 3 of 27	ENSP00000498903.1	Q9NQ90-1
	ANO2	ENST00000356134.9	TSL:5	c.254G>A	p.Arg85His	missense	Exon 3 of 27	ENSP00000348453.5	Q9NQ90-2

Frequencies

GnomAD3 genomes AF: 0.00254 AC: 386 AN: 152104 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00775

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00950

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000967 AC: 241 AN: 249184 AF XY: 0.000806

Gnomad AFR exome AF: 0.00853

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.00746

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.000827

GnomAD4 exome AF: 0.000471 AC: 689 AN: 1461694 Hom.: 2 Cov.: 34 AF XY: 0.000424 AC XY: 308 AN XY: 727132

African (AFR) AF: 0.00780 AC: 261 AN: 33480

American (AMR) AF: 0.000380 AC: 17 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00869 AC: 227 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86254

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

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.0000980 AC: 109 AN: 1111866

Other (OTH) AF: 0.00114 AC: 69 AN: 60374

GnomAD4 genome AF: 0.00254 AC: 387 AN: 152222 Hom.: 5 Cov.: 32 AF XY: 0.00258 AC XY: 192 AN XY: 74414

African (AFR) AF: 0.00775 AC: 322 AN: 41524

American (AMR) AF: 0.000980 AC: 15 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00950 AC: 33 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

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

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: 0.000191 AC: 13 AN: 68016

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00132 Hom.: 3

Bravo AF: 0.00274

ESP6500AA AF: 0.00719 AC: 30

ESP6500EA AF: 0.000474 AC: 4

ExAC AF: 0.000892 AC: 108

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.096	T
Eigen	Benign	-0.036
Eigen_PC	Benign	-0.042
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.0060	T
MetaSVM	Benign	-0.61	T
PhyloP100		1.2
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.33	N
REVEL	Benign	0.17
Sift	Benign	0.23	T
Sift4G	Benign	0.15	T
Vest4		0.18
MVP		0.29
MPC		0.080
ClinPred		0.014	T
GERP RS		4.2
gMVP		0.24
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: rs182999590; hg19: chr12-6030474; COSMIC: COSV59022759;