NM_001025356.3:c.2674G>C

Variant names:

• chr12-45429252-G-C
• rs60329053
• NM_001025356.3:c.2674G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001025356.3(ANO6):​c.2674G>C​(p.Val892Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00329 in 1,613,900 control chromosomes in the GnomAD database, including 155 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.018 (80 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (75 hom.)
• Consequence: ANO6 NM_001025356.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.469
• Publications: 7 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: Ambry Genetics, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)

ENSG00000293678 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001354903).
• BP6: Variant 12-45429252-G-C is Benign according to our data. Variant chr12-45429252-G-C is described in ClinVar as Benign. ClinVar VariationId is 257145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0604 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANO6	NM_001025356.3	MANE Select	c.2674G>C	p.Val892Leu	missense	Exon 20 of 20	NP_001020527.2
	ANO6	NM_001204803.2		c.2737G>C	p.Val913Leu	missense	Exon 21 of 21	NP_001191732.1
	ANO6	NM_001410973.1		c.2641G>C	p.Val881Leu	missense	Exon 20 of 20	NP_001397902.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANO6	ENST00000320560.13	TSL:1 MANE Select	c.2674G>C	p.Val892Leu	missense	Exon 20 of 20	ENSP00000320087.8
	ANO6	ENST00000423947.7	TSL:1	c.2737G>C	p.Val913Leu	missense	Exon 21 of 21	ENSP00000409126.3
	ANO6	ENST00000441606.2	TSL:1	c.2620G>C	p.Val874Leu	missense	Exon 20 of 20	ENSP00000413137.2

Frequencies

GnomAD3 genomes AF: 0.0181 AC: 2747 AN: 152186 Hom.: 79 Cov.: 32

Gnomad AFR AF: 0.0625

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00805

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: 0.000103

Gnomad OTH AF: 0.0129

GnomAD2 exomes AF: 0.00495 AC: 1240 AN: 250602 AF XY: 0.00319

Gnomad AFR exome AF: 0.0691

Gnomad AMR exome AF: 0.00284

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000795

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00175 AC: 2556 AN: 1461596 Hom.: 75 Cov.: 31 AF XY: 0.00137 AC XY: 995 AN XY: 727098

African (AFR) AF: 0.0639 AC: 2140 AN: 33468

American (AMR) AF: 0.00342 AC: 153 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39640

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53362

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5764

European-Non Finnish (NFE) AF: 0.0000297 AC: 33 AN: 1111894

Other (OTH) AF: 0.00346 AC: 209 AN: 60380

GnomAD4 genome AF: 0.0181 AC: 2751 AN: 152304 Hom.: 80 Cov.: 32 AF XY: 0.0174 AC XY: 1295 AN XY: 74472

African (AFR) AF: 0.0624 AC: 2594 AN: 41546

American (AMR) AF: 0.00804 AC: 123 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68028

Other (OTH) AF: 0.0128 AC: 27 AN: 2114

Alfa AF: 0.00124 Hom.: 1

Bravo AF: 0.0215

ESP6500AA AF: 0.0708 AC: 312

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00641 AC: 778

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	9.1
DANN	Benign	0.88
DEOGEN2	Benign	0.031	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.47
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.080	N
REVEL	Benign	0.057
Sift	Benign	0.32	T
Sift4G	Benign	0.74	T
Polyphen		0.0010	B
Vest4		0.035
MutPred		0.27		Loss of catalytic residue at V892 (P = 0.0987)
MVP		0.44
MPC		0.18
ClinPred		0.00082	T
GERP RS		-2.1
Varity_R		0.024
gMVP		0.23
Mutation Taster		=99/1	polymorphism (auto)

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: rs60329053; hg19: chr12-45823035;