rs4108250

Variant names:

• chr12-45350652-G-A
• rs4108250
• NM_001025356.3:c.748-7G>A

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.748-7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00738 in 1,610,230 control chromosomes in the GnomAD database, including 480 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (244 hom., cov: 32)
  • Exomes 𝑓: 0.0047 (236 hom.)
• Consequence: ANO6 NM_001025356.3 splice_region, intron
• Scores: Splicing: ADA: 0.00001468
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.52
• Publications: 3 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 12-45350652-G-A is Benign according to our data. Variant chr12-45350652-G-A is described in ClinVar as Benign. ClinVar VariationId is 257147.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.

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.748-7G>A		splice_region intron	N/A	NP_001020527.2	Q4KMQ2-1
	ANO6	NM_001204803.2		c.811-7G>A		splice_region intron	N/A	NP_001191732.1	Q4KMQ2-2
	ANO6	NM_001142679.2		c.748-7G>A		splice_region intron	N/A	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.748-7G>A		splice_region intron	N/A	ENSP00000320087.8	Q4KMQ2-1
	ANO6	ENST00000423947.7	TSL:1	c.811-7G>A		splice_region intron	N/A	ENSP00000409126.3	Q4KMQ2-2
	ANO6	ENST00000425752.6	TSL:1	c.748-7G>A		splice_region intron	N/A	ENSP00000391417.2	Q4KMQ2-4

Frequencies

GnomAD3 genomes AF: 0.0329 AC: 4997 AN: 152092 Hom.: 241 Cov.: 32

Gnomad AFR AF: 0.109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0175

Gnomad ASJ AF: 0.00836

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00725

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00116

Gnomad OTH AF: 0.0278

GnomAD2 exomes AF: 0.0103 AC: 2568 AN: 250526 AF XY: 0.00779

Gnomad AFR exome AF: 0.116

Gnomad AMR exome AF: 0.00612

Gnomad ASJ exome AF: 0.0110

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000997

Gnomad OTH exome AF: 0.00507

GnomAD4 exome AF: 0.00471 AC: 6864 AN: 1458020 Hom.: 236 Cov.: 30 AF XY: 0.00425 AC XY: 3083 AN XY: 725556

African (AFR) AF: 0.112 AC: 3737 AN: 33382

American (AMR) AF: 0.00730 AC: 326 AN: 44638

Ashkenazi Jewish (ASJ) AF: 0.0113 AC: 294 AN: 26080

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39648

South Asian (SAS) AF: 0.00664 AC: 572 AN: 86080

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53382

Middle Eastern (MID) AF: 0.00573 AC: 33 AN: 5760

European-Non Finnish (NFE) AF: 0.00121 AC: 1345 AN: 1108782

Other (OTH) AF: 0.00919 AC: 554 AN: 60268

GnomAD4 genome AF: 0.0330 AC: 5017 AN: 152210 Hom.: 244 Cov.: 32 AF XY: 0.0316 AC XY: 2352 AN XY: 74428

African (AFR) AF: 0.110 AC: 4549 AN: 41490

American (AMR) AF: 0.0175 AC: 267 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00836 AC: 29 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00725 AC: 35 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

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

European-Non Finnish (NFE) AF: 0.00116 AC: 79 AN: 68026

Other (OTH) AF: 0.0275 AC: 58 AN: 2112

Alfa AF: 0.0143 Hom.: 266

Bravo AF: 0.0381

Asia WGS AF: 0.0100 AC: 36 AN: 3478

EpiCase AF: 0.000981

EpiControl AF: 0.000950

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	3.0
DANN	Benign	0.59
PhyloP100		1.5
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000015
dbscSNV1_RF	Benign	0.0
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: rs4108250; hg19: chr12-45744435;