Variant 12-100942466-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2PP5_ModerateBP4

The NM_001286615.2(ANO4):c.387C>G(p.Asn129Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ANO4
NM_001286615.2 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 1.30

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]

ANO4 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 12-100942466-C-G is Pathogenic according to our data. Variant chr12-100942466-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 3067135.Status of the report is criteria_provided_single_submitter, 1 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.16623384). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANO4	NM_001286615.2 linkuse as main transcript	c.387C>G	p.Asn129Lys	missense_variant	5/28	ENST00000392977.8	NP_001273544.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANO4	ENST00000392977.8 linkuse as main transcript	c.387C>G	p.Asn129Lys	missense_variant	5/28	2	NM_001286615.2	ENSP00000376703		Q32M45-1
ANO4	ENST00000644049.1 linkuse as main transcript	c.885C>G	p.Asn295Lys	missense_variant	7/30			ENSP00000494481
ANO4	ENST00000392979.7 linkuse as main transcript	c.282C>G	p.Asn94Lys	missense_variant	4/27	2		ENSP00000376705	P1	Q32M45-2
ANO4	ENST00000549155.6 linkuse as main transcript	c.885C>G	p.Asn295Lys	missense_variant, NMD_transcript_variant	7/11	2		ENSP00000449116

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461770

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727202

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts

Pathogenic:1

Pathogenic, criteria provided, single submitter

in vitro;research

Institute of Medical Genetics, University of Zurich

Mar 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.50

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.051

.;.;T

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.016

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Benign

0.016

MetaRNN

Benign

0.17

T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.0

.;.;L

MutationTaster

Benign

0.77

D;D;D;D

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-1.0

.;N;N

REVEL

Benign

0.045

Sift

Benign

0.15

.;T;T

Sift4G

Benign

0.26

.;T;T

Polyphen

0.43, 0.019

.;B;B

Vest4

0.30, 0.26

MutPred

0.43

.;.;Gain of methylation at N129 (P = 0.0087);

MVP

0.043

MPC

0.85

ClinPred

0.53

GERP RS

3.8

Varity_R

0.14

gMVP

0.21

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over