chr12-100942466-C-A

Variant names:

• chr12-100942466-C-A
• rs1224091418
• NM_001286615.2:c.387C>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 7P and 2B. PS1 PM2 PP2 BP4_Moderate

The NM_001286615.2(ANO4):​c.387C>A​(p.Asn129Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,018 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: ANO4 NM_001286615.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.30
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PS1: Transcript NM_001286615.2 (ANO4) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 3067135
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 7 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 2.5332 (below the threshold of 3.09). Trascript score misZ: 3.1552 (above the threshold of 3.09). GenCC associations: The gene is linked to complex neurodevelopmental disorder.
• BP4: Computational evidence support a benign effect (MetaRNN=0.16578361).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANO4	NM_001286615.2	c.387C>A	p.Asn129Lys	missense_variant	Exon 5 of 28	ENST00000392977.8	NP_001273544.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANO4	ENST00000392977.8	c.387C>A	p.Asn129Lys	missense_variant	Exon 5 of 28	2	NM_001286615.2	ENSP00000376703.3
ANO4	ENST00000644049.1	c.885C>A	p.Asn295Lys	missense_variant	Exon 7 of 30			ENSP00000494481.1
ANO4	ENST00000392979.7	c.282C>A	p.Asn94Lys	missense_variant	Exon 4 of 27	2		ENSP00000376705.3
ANO4	ENST00000549155.6	n.885C>A		non_coding_transcript_exon_variant	Exon 7 of 11	2		ENSP00000449116.2

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152018 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152018 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74218

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41374

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2086

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000712 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.051	.;.;T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.016
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.17	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.0	.;.;L
PhyloP100		1.3
PrimateAI	Uncertain	0.51	T
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	D
GERP RS		3.8
Varity_R		0.14
gMVP		0.21
Mutation Taster		=66/34	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

Other links and lift over

dbSNP: rs1224091418; hg19: chr12-101336244;