chr12-100942399-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The NM_001286615.2(ANO4):​c.320C>T​(p.Ser107Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000403 in 1,613,766 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000041 ( 0 hom. )

Consequence

ANO4
NM_001286615.2 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.46
Variant links:
Genes affected
ANO4 (HGNC:23837): (anoctamin 4) Enables intracellular calcium activated chloride channel activity. Involved in chloride transport. Located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.043947548).
BS1
Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.0000411 (60/1461588) while in subpopulation AMR AF= 0.0000672 (3/44676). AF 95% confidence interval is 0.0000212. There are 0 homozygotes in gnomad4_exome. There are 30 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ANO4NM_001286615.2 linkc.320C>T p.Ser107Leu missense_variant Exon 5 of 28 ENST00000392977.8 NP_001273544.1 Q32M45-1B7Z9Z0

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ANO4ENST00000392977.8 linkc.320C>T p.Ser107Leu missense_variant Exon 5 of 28 2 NM_001286615.2 ENSP00000376703.3 Q32M45-1
ANO4ENST00000644049.1 linkc.818C>T p.Ser273Leu missense_variant Exon 7 of 30 ENSP00000494481.1 A0A2R8Y532
ANO4ENST00000392979.7 linkc.215C>T p.Ser72Leu missense_variant Exon 4 of 27 2 ENSP00000376705.3 Q32M45-2
ANO4ENST00000549155.6 linkn.818C>T non_coding_transcript_exon_variant Exon 7 of 11 2 ENSP00000449116.2 F8VW62

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152178
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00115
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000558
AC:
14
AN:
250920
Hom.:
0
AF XY:
0.0000664
AC XY:
9
AN XY:
135604
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.000398
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000617
Gnomad OTH exome
AF:
0.000164
GnomAD4 exome
AF:
0.0000411
AC:
60
AN:
1461588
Hom.:
0
Cov.:
30
AF XY:
0.0000413
AC XY:
30
AN XY:
727090
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000672
Gnomad4 ASJ exome
AF:
0.000651
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000297
Gnomad4 OTH exome
AF:
0.0000994
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
152178
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74338
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00115
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000135
Hom.:
0
Bravo
AF:
0.0000416
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000494
AC:
6
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Dec 27, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.215C>T (p.S72L) alteration is located in exon 4 (coding exon 3) of the ANO4 gene. This alteration results from a C to T substitution at nucleotide position 215, causing the serine (S) at amino acid position 72 to be replaced by a leucine (L). 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
0.083
BayesDel_addAF
Benign
-0.38
T
BayesDel_noAF
Benign
-0.60
CADD
Benign
19
DANN
Benign
0.93
DEOGEN2
Benign
0.070
.;.;T
Eigen
Benign
-0.78
Eigen_PC
Benign
-0.64
FATHMM_MKL
Uncertain
0.80
D
LIST_S2
Benign
0.81
T;T;T
M_CAP
Benign
0.019
T
MetaRNN
Benign
0.044
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.4
.;.;L
PrimateAI
Benign
0.44
T
PROVEAN
Benign
-1.2
.;N;N
REVEL
Benign
0.020
Sift
Benign
0.50
.;T;T
Sift4G
Benign
0.43
.;T;T
Polyphen
0.23, 0.15
.;B;B
Vest4
0.19, 0.15
MVP
0.043
MPC
0.53
ClinPred
0.28
T
GERP RS
1.7
Varity_R
0.047
gMVP
0.22

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs141833422; hg19: chr12-101336177; API