12-101086811-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Moderate PP5_Moderate

The NM_001286615.2(ANO4):c.1688T>A(p.Met563Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ANO4 NM_001286615.2 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.02

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, ANO4
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.897
• PP5: Variant 12-101086811-T-A is Pathogenic according to our data. Variant chr12-101086811-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 3067131.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANO4	NM_001286615.2	c.1688T>A	p.Met563Lys	missense_variant	17/28	ENST00000392977.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANO4	ENST00000392977.8	c.1688T>A	p.Met563Lys	missense_variant	17/28	2	NM_001286615.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
Cadd	Pathogenic	29
Dann	Uncertain	0.99
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.90	D;D;D
MetaSVM	Uncertain	-0.024	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.89	D
Polyphen		0.89, 0.91	.;P;P
Vest4		0.96, 0.97
MutPred		0.72		.;.;Loss of stability (P = 0.0126);
MVP		0.15
MPC		1.6
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.95
gMVP		0.99

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

Other links and lift over

dbSNP: rs2049522225; hg19: chr12-101480589;