12-45348064-G-A

Position:

• chr12-45348064-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001025356.3(ANO6):​c.382G>A​(p.Ala128Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00655 in 1,613,824 control chromosomes in the GnomAD database, including 481 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.033 (248 hom., cov: 32)
  • Exomes 𝑓: 0.0038 (233 hom.)
• Consequence: ANO6 NM_001025356.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.22

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003555566).
• BP6: Variant 12-45348064-G-A is Benign according to our data. Variant chr12-45348064-G-A is described in ClinVar as [Benign]. Clinvar id is 257146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.107 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANO6	NM_001025356.3	c.382G>A	p.Ala128Thr	missense_variant	5/20	ENST00000320560.13	NP_001020527.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANO6	ENST00000320560.13	c.382G>A	p.Ala128Thr	missense_variant	5/20	1	NM_001025356.3	ENSP00000320087	P4

Frequencies

GnomAD3 genomes AF: 0.0324 AC: 4932 AN: 152012 Hom.: 245 Cov.: 32

Gnomad AFR AF: 0.110

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0163

Gnomad ASJ AF: 0.00692

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00726

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.0272

GnomAD3 exomes AF: 0.00976 AC: 2451 AN: 251078 Hom.: 113 AF XY: 0.00734 AC XY: 996 AN XY: 135712

Gnomad AFR exome AF: 0.116

Gnomad AMR exome AF: 0.00567

Gnomad ASJ exome AF: 0.00854

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00722

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000256

Gnomad OTH exome AF: 0.00441

GnomAD4 exome AF: 0.00384 AC: 5618 AN: 1461694 Hom.: 233 Cov.: 31 AF XY: 0.00342 AC XY: 2489 AN XY: 727148

Gnomad4 AFR exome AF: 0.112

Gnomad4 AMR exome AF: 0.00685

Gnomad4 ASJ exome AF: 0.00953

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00667

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000211

Gnomad4 OTH exome AF: 0.00788

GnomAD4 genome AF: 0.0325 AC: 4948 AN: 152130 Hom.: 248 Cov.: 32 AF XY: 0.0310 AC XY: 2309 AN XY: 74370

Gnomad4 AFR AF: 0.110

Gnomad4 AMR AF: 0.0162

Gnomad4 ASJ AF: 0.00692

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00727

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.0270

Alfa AF: 0.00782 Hom.: 79

Bravo AF: 0.0374

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.112 AC: 495

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.0119 AC: 1446

Asia WGS AF: 0.0100 AC: 36 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	.;.;T;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	D;D;D;D
MetaRNN	Benign	0.0036	T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Pathogenic	3.1	M;.;M;.
MutationTaster	Benign	0.0011	P;P;P;P;P
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.1	D;D;D;D
REVEL	Benign	0.21
Sift	Uncertain	0.020	D;T;T;T
Sift4G	Benign	0.077	T;T;T;T
Polyphen		1.0	.;.;D;.
Vest4		0.29
MPC		0.38
ClinPred		0.044	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.16
gMVP		0.71

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: rs2162321; hg19: chr12-45741847;