12-100922312-C-T

Variant names:

• chr12-100922312-C-T
• NM_001286615.2:c.142C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001286615.2(ANO4):​c.142C>T​(p.Leu48Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000029 in 1,378,084 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: ANO4 NM_001286615.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.68

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28704062).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANO4	NM_001286615.2	c.142C>T	p.Leu48Phe	missense_variant	Exon 3 of 28	ENST00000392977.8	NP_001273544.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANO4	ENST00000392977.8	c.142C>T	p.Leu48Phe	missense_variant	Exon 3 of 28	2	NM_001286615.2	ENSP00000376703.3
ANO4	ENST00000644049.1	c.640C>T	p.Leu214Phe	missense_variant	Exon 5 of 30			ENSP00000494481.1
ANO4	ENST00000392979.7	c.56-17003C>T		intron_variant	Intron 2 of 26	2		ENSP00000376705.3
ANO4	ENST00000549155.6	n.640C>T		non_coding_transcript_exon_variant	Exon 5 of 11	2		ENSP00000449116.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000290 AC: 4 AN: 1378084 Hom.: 0 Cov.: 30 AF XY: 0.00000441 AC XY: 3 AN XY: 680160

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000512

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Sep 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 48 of the ANO4 protein (p.Leu48Phe). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ANO4-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.021	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.038	.;T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.75	T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.29	T;T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	1.0	.;L
PROVEAN	Benign	-0.68	.;N
REVEL	Benign	0.20
Sift	Benign	0.66	.;T
Sift4G	Benign	0.17	.;T
Polyphen		0.82	.;P
Vest4		0.38
MutPred		0.30		.;Loss of stability (P = 0.1859);
MVP		0.043
ClinPred		0.88	D
GERP RS		5.7
Varity_R		0.16
gMVP		0.094

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.

Other links and lift over

hg19: chr12-101316090;