chr12-45302086-C-G

Variant names:

• chr12-45302086-C-G
• rs770877324
• NM_001025356.3:c.143C>G

Variant summary

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

The NM_001025356.3(ANO6):​c.143C>G​(p.Pro48Arg) 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 1,461,496 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. P48L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ANO6 NM_001025356.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.45
• Publications: 1 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=0.28719413).

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.143C>G	p.Pro48Arg	missense	Exon 2 of 20	NP_001020527.2	Q4KMQ2-1
	ANO6	NM_001204803.2		c.206C>G	p.Pro69Arg	missense	Exon 3 of 21	NP_001191732.1	Q4KMQ2-2
	ANO6	NM_001142679.2		c.143C>G	p.Pro48Arg	missense	Exon 2 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.143C>G	p.Pro48Arg	missense	Exon 2 of 20	ENSP00000320087.8	Q4KMQ2-1
	ANO6	ENST00000423947.7	TSL:1	c.206C>G	p.Pro69Arg	missense	Exon 3 of 21	ENSP00000409126.3	Q4KMQ2-2
	ANO6	ENST00000425752.6	TSL:1	c.143C>G	p.Pro48Arg	missense	Exon 2 of 20	ENSP00000391417.2	Q4KMQ2-4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251252 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461496 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727060

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

African (AFR) AF: 0.00 AC: 0 AN: 33454

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111722

Other (OTH) AF: 0.00 AC: 0 AN: 60372

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Benign	0.0084	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.083	T
Eigen	Benign	-0.0026
Eigen_PC	Benign	0.056
FATHMM_MKL	Benign	0.60	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.29	T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	0.81	L
PhyloP100		3.5
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.13
Sift	Uncertain	0.029	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.29	B
Vest4		0.47
MutPred		0.23		Gain of helix (P = 0.0082)
MVP		0.45
MPC		0.20
ClinPred		0.70	D
GERP RS		4.8
Varity_R		0.10
gMVP		0.39
Mutation Taster		=73/27	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: rs770877324; hg19: chr12-45695869;