11-70087921-G-T

Variant names:

• chr11-70087921-G-T
• rs372506351
• NM_018043.7:c.278G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_018043.7(ANO1):​c.278G>T​(p.Arg93Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000055 in 1,455,540 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: ANO1 NM_018043.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.15
• Publications: 0 publications found

Genes affected

ANO1 (HGNC:21625): (anoctamin 1) Enables calcium activated cation channel activity; intracellular calcium activated chloride channel activity; and iodide transmembrane transporter activity. Involved in cation transport; inorganic anion transport; and positive regulation of insulin secretion involved in cellular response to glucose stimulus. Located in apical plasma membrane and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ANO1 Gene-Disease associations (from GenCC):

• moyamoya disease 7

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• intestinal dysmotility syndrome

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14895216).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018043.7. 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
	ANO1	NM_018043.7	MANE Select	c.278G>T	p.Arg93Leu	missense	Exon 2 of 26	NP_060513.5
	ANO1	NM_001378092.1		c.401G>T	p.Arg134Leu	missense	Exon 3 of 28	NP_001365021.1	Q5XXA6-5
	ANO1	NM_001378093.1		c.278G>T	p.Arg93Leu	missense	Exon 3 of 26	NP_001365022.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANO1	ENST00000355303.10	TSL:1 MANE Select	c.278G>T	p.Arg93Leu	missense	Exon 2 of 26	ENSP00000347454.5	Q5XXA6-1
	ANO1	ENST00000531349.6	TSL:1	c.401G>T	p.Arg134Leu	missense	Exon 3 of 28	ENSP00000432843.2	Q5XXA6-5
	ANO1	ENST00000930664.1		c.278G>T	p.Arg93Leu	missense	Exon 3 of 26	ENSP00000600723.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000550 AC: 8 AN: 1455540 Hom.: 0 Cov.: 31 AF XY: 0.00000553 AC XY: 4 AN XY: 723514

African (AFR) AF: 0.00 AC: 0 AN: 33394

American (AMR) AF: 0.00 AC: 0 AN: 44068

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25968

East Asian (EAS) AF: 0.0000506 AC: 2 AN: 39504

South Asian (SAS) AF: 0.00 AC: 0 AN: 85104

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52242

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5758

European-Non Finnish (NFE) AF: 0.00000361 AC: 4 AN: 1109364

Other (OTH) AF: 0.00 AC: 0 AN: 60138

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.096	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	20
DANN	Benign	0.92
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		2.2
PrimateAI	Benign	0.48	T
PROVEAN	Benign	0.25	N
REVEL	Benign	0.079
Sift	Benign	0.27	T
Sift4G	Benign	0.31	T
Polyphen		0.58	P
Vest4		0.59
MutPred		0.35		Loss of helix (P = 0.0123)
MVP		0.60
MPC		0.83
ClinPred		0.67	D
GERP RS		0.95
Varity_R		0.071
gMVP		0.45
Mutation Taster		=258/42	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: rs372506351; hg19: chr11-69934027;