11-70088078-C-G

Variant names:

• chr11-70088078-C-G
• rs542259870
• NM_018043.7:c.435C>G

Variant summary

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

The NM_018043.7(ANO1):​c.435C>G​(p.Asp145Glu) 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 1,219,232 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. D145D) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: ANO1 NM_018043.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.251
• 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: 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=0.1660085).

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.435C>G	p.Asp145Glu	missense	Exon 2 of 26	NP_060513.5
	ANO1	NM_001378092.1		c.558C>G	p.Asp186Glu	missense	Exon 3 of 28	NP_001365021.1	Q5XXA6-5
	ANO1	NM_001378093.1		c.435C>G	p.Asp145Glu	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.435C>G	p.Asp145Glu	missense	Exon 2 of 26	ENSP00000347454.5	Q5XXA6-1
	ANO1	ENST00000531349.6	TSL:1	c.558C>G	p.Asp186Glu	missense	Exon 3 of 28	ENSP00000432843.2	Q5XXA6-5
	ANO1	ENST00000930664.1		c.435C>G	p.Asp145Glu	missense	Exon 3 of 26	ENSP00000600723.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000410 AC: 5 AN: 1219232 Hom.: 0 Cov.: 34 AF XY: 0.00000341 AC XY: 2 AN XY: 586486

African (AFR) AF: 0.00 AC: 0 AN: 25614

American (AMR) AF: 0.00 AC: 0 AN: 13984

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17174

East Asian (EAS) AF: 0.0000336 AC: 1 AN: 29740

South Asian (SAS) AF: 0.00 AC: 0 AN: 46952

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43044

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4940

European-Non Finnish (NFE) AF: 0.00000405 AC: 4 AN: 987900

Other (OTH) AF: 0.00 AC: 0 AN: 49884

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		-0.25
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.12
Sift	Benign	0.27	T
Sift4G	Benign	0.84	T
Polyphen		0.97	D
Vest4		0.28
MutPred		0.20		Loss of ubiquitination at K149 (P = 0.1121)
MVP		0.47
MPC		0.41
ClinPred		0.87	D
GERP RS		0.14
Varity_R		0.14
gMVP		0.39
Mutation Taster		=77/23	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs542259870; hg19: chr11-69934184;