chr11-70087960-C-T

Variant names:

• chr11-70087960-C-T
• rs373880950
• NM_018043.7:c.317C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_018043.7(ANO1):​c.317C>T​(p.Ala106Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000277 in 1,589,438 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: ANO1 NM_018043.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.143

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]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.046578556).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANO1	NM_018043.7	c.317C>T	p.Ala106Val	missense_variant	Exon 2 of 26	ENST00000355303.10	NP_060513.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANO1	ENST00000355303.10	c.317C>T	p.Ala106Val	missense_variant	Exon 2 of 26	1	NM_018043.7	ENSP00000347454.5

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152048 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.0000693 AC: 15 AN: 216564 AF XY: 0.0000676

Gnomad AFR exome AF: 0.0000780

Gnomad AMR exome AF: 0.000292

Gnomad ASJ exome AF: 0.000329

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000104

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000244 AC: 35 AN: 1437272 Hom.: 0 Cov.: 31 AF XY: 0.0000253 AC XY: 18 AN XY: 711862

African (AFR) AF: 0.0000303 AC: 1 AN: 33032

American (AMR) AF: 0.000308 AC: 13 AN: 42212

Ashkenazi Jewish (ASJ) AF: 0.000314 AC: 8 AN: 25496

East Asian (EAS) AF: 0.00 AC: 0 AN: 38718

South Asian (SAS) AF: 0.0000121 AC: 1 AN: 82790

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51536

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5704

European-Non Finnish (NFE) AF: 0.00000728 AC: 8 AN: 1098450

Other (OTH) AF: 0.0000506 AC: 3 AN: 59334

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152166 Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2 AN XY: 74394

African (AFR) AF: 0.0000241 AC: 1 AN: 41536

American (AMR) AF: 0.000196 AC: 3 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5134

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67978

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.0000497 Hom.: 0

Bravo AF: 0.0000491

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000415 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 16, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.317C>T (p.A106V) alteration is located in exon 2 (coding exon 2) of the ANO1 gene. This alteration results from a C to T substitution at nucleotide position 317, causing the alanine (A) at amino acid position 106 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	0.081
DANN	Benign	0.87
DEOGEN2	Benign	0.12	T;.;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.53	T;T;T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.047	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.20	N;.;.
PhyloP100		-0.14
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.33	N;N;N
REVEL	Benign	0.040
Sift	Benign	0.21	T;T;T
Sift4G	Benign	0.42	T;T;T
Polyphen		0.0	B;.;B
Vest4		0.041
MVP		0.53
MPC		0.41
ClinPred		0.0086	T
GERP RS		0.084
Varity_R		0.027
gMVP		0.19
Mutation Taster		=289/11	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

Publications

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Other links and lift over

dbSNP: rs373880950; hg19: chr11-69934066; COSMIC: COSV60281316;