rs142960268

Positions:

• chr12-45388269-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001025356.3(ANO6):​c.1274G>A​(p.Arg425Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00251 in 1,614,100 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0017 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (6 hom.)
• Consequence: ANO6 NM_001025356.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.324

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0103028715).
• BP6: Variant 12-45388269-G-A is Benign according to our data. Variant chr12-45388269-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 257140.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00166 (253/152288) while in subpopulation NFE AF= 0.00281 (191/68030). AF 95% confidence interval is 0.00248. There are 1 homozygotes in gnomad4. There are 116 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANO6	NM_001025356.3	c.1274G>A	p.Arg425Gln	missense_variant	11/20	ENST00000320560.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANO6	ENST00000320560.13	c.1274G>A	p.Arg425Gln	missense_variant	11/20	1	NM_001025356.3	P4

Frequencies

GnomAD3 genomes AF: 0.00166 AC: 253 AN: 152170 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00281

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00131 AC: 330 AN: 251450 Hom.: 0 AF XY: 0.00138 AC XY: 187 AN XY: 135894

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.000983

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00240

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00260 AC: 3805 AN: 1461812 Hom.: 6 Cov.: 31 AF XY: 0.00248 AC XY: 1800 AN XY: 727208

Gnomad4 AFR exome AF: 0.000597

Gnomad4 AMR exome AF: 0.00112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000927

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.00322

Gnomad4 OTH exome AF: 0.00222

GnomAD4 genome AF: 0.00166 AC: 253 AN: 152288 Hom.: 1 Cov.: 32 AF XY: 0.00156 AC XY: 116 AN XY: 74468

Gnomad4 AFR AF: 0.000602

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00281

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00226 Hom.: 2

Bravo AF: 0.00190

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00256 AC: 22

ExAC AF: 0.00127 AC: 154

EpiCase AF: 0.00213

EpiControl AF: 0.00255

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 04, 2023	Variant summary: ANO6 c.1274G>A (p.Arg425Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0013 in 282850 control chromosomes in the gnomAD database, including 1 homozygotes. However, this gnomad data is not considered conclusive as Scott Syndrome may be a clinically silent disease. To our knowledge, no occurrence of c.1274G>A in individuals affected with Scott Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as benign. Based on the evidence outlined above, the variant was classified as VUS. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 03, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	14
DANN	Uncertain	0.99
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.81	T;T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.010	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.91	L;.;L;.
MutationTaster	Benign	0.82	N;N;N;N;N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	0.35	N;N;N;N
REVEL	Benign	0.014
Sift	Benign	0.15	T;T;T;T
Sift4G	Benign	0.22	T;T;T;T
Polyphen		0.48	.;.;P;.
Vest4		0.24
MVP		0.38
MPC		0.22
ClinPred		0.0082	T
GERP RS		0.20
Varity_R		0.024
gMVP		0.28

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

Publications

LitVar

Other links and lift over

dbSNP: rs142960268; hg19: chr12-45782052; COSMIC: COSV57659758;