11-70078697-C-A

Variant names:

• chr11-70078697-C-A
• rs765946675
• NM_018043.7:c.91C>A

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.91C>A​(p.Leu31Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000748 in 1,337,244 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. L31V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: ANO1 NM_018043.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.28
• 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]

LINC02584 (HGNC:33275): (long intergenic non-protein coding RNA 2584)

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=0.21825603).

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.91C>A	p.Leu31Met	missense	Exon 1 of 26	NP_060513.5
	ANO1	NM_001378092.1		c.214C>A	p.Leu72Met	missense	Exon 2 of 28	NP_001365021.1	Q5XXA6-5
	ANO1	NM_001378093.1		c.91C>A	p.Leu31Met	missense	Exon 2 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.91C>A	p.Leu31Met	missense	Exon 1 of 26	ENSP00000347454.5	Q5XXA6-1
	ANO1	ENST00000531349.6	TSL:1	c.214C>A	p.Leu72Met	missense	Exon 2 of 28	ENSP00000432843.2	Q5XXA6-5
	ANO1	ENST00000930664.1		c.91C>A	p.Leu31Met	missense	Exon 2 of 26	ENSP00000600723.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.48e-7 AC: 1 AN: 1337244 Hom.: 0 Cov.: 30 AF XY: 0.00000150 AC XY: 1 AN XY: 665672

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26572

American (AMR) AF: 0.00 AC: 0 AN: 36102

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21300

East Asian (EAS) AF: 0.00 AC: 0 AN: 27892

South Asian (SAS) AF: 0.00 AC: 0 AN: 79966

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47794

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5220

European-Non Finnish (NFE) AF: 9.62e-7 AC: 1 AN: 1039980

Other (OTH) AF: 0.00 AC: 0 AN: 52418

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.80	T
M_CAP	Pathogenic	0.80	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.3
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.13	N
REVEL	Benign	0.057
Sift	Benign	0.12	T
Sift4G	Benign	0.13	T
Polyphen		0.51	P
Vest4		0.14
MutPred		0.37		Loss of helix (P = 0.0068)
MVP		0.36
MPC		0.65
ClinPred		0.28	T
GERP RS		3.4
PromoterAI		0.19	Neutral
Varity_R		0.15
gMVP		0.23
Mutation Taster		=92/8	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: rs765946675; hg19: chr11-69924803;