12-45388269-G-T

Variant names:

• chr12-45388269-G-T
• rs142960268
• NM_001025356.3:c.1274G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001025356.3(ANO6):​c.1274G>T​(p.Arg425Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R425Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ANO6 NM_001025356.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.324
• Publications: 0 publications found

Genes affected

ANO6 (HGNC:25240): (anoctamin 6) This gene encodes a multi-pass transmembrane protein that belongs to the anoctamin family. This protein is an essential component for the calcium-dependent exposure of phosphatidylserine on the cell surface. The scrambling of phospholipid occurs in various biological systems, such as when blood platelets are activated, they expose phosphatidylserine to trigger the clotting system. Mutations in this gene are associated with Scott syndrome. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Mar 2011]

ANO6 Gene-Disease associations (from GenCC):

• Scott syndrome

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Orphanet

ENSG00000293678 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26409578).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001025356.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANO6	NM_001025356.3	MANE Select	c.1274G>T	p.Arg425Leu	missense	Exon 11 of 20	NP_001020527.2	Q4KMQ2-1
	ANO6	NM_001204803.2		c.1337G>T	p.Arg446Leu	missense	Exon 12 of 21	NP_001191732.1	Q4KMQ2-2
	ANO6	NM_001142679.2		c.1274G>T	p.Arg425Leu	missense	Exon 11 of 20	NP_001136151.1	Q4KMQ2-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANO6	ENST00000320560.13	TSL:1 MANE Select	c.1274G>T	p.Arg425Leu	missense	Exon 11 of 20	ENSP00000320087.8	Q4KMQ2-1
	ANO6	ENST00000423947.7	TSL:1	c.1337G>T	p.Arg446Leu	missense	Exon 12 of 21	ENSP00000409126.3	Q4KMQ2-2
	ANO6	ENST00000425752.6	TSL:1	c.1274G>T	p.Arg425Leu	missense	Exon 11 of 20	ENSP00000391417.2	Q4KMQ2-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461812 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727208

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111960

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.30	N
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.32
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.029
Sift	Uncertain	0.024	D
Sift4G	Benign	0.068	T
Polyphen		0.43	B
Vest4		0.51
MutPred		0.48		Loss of disorder (P = 0.0526)
MVP		0.41
MPC		0.44
ClinPred		0.57	D
GERP RS		0.20
Varity_R		0.081
gMVP		0.54
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs142960268; hg19: chr12-45782052;