NM_213599.3:c.294G>A

Variant names:

• chr11-22221210-G-A
• rs142858990
• NM_213599.3:c.294G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Moderate BP6 BP7

The NM_213599.3(ANO5):​c.294G>A​(p.Ala98Ala) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000677 in 1,592,724 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00061 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00068 (0 hom.)
• Consequence: ANO5 NM_213599.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.1920
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:3
• Conservation: PhyloP100: 2.14
• Publications: 3 publications found

Genes affected

ANO5 (HGNC:27337): (anoctamin 5) This gene encodes a member of the anoctamin family of transmembrane proteins. The encoded protein is likely a calcium activated chloride channel. Mutations in this gene have been associated with gnathodiaphyseal dysplasia. Alternatively spliced transcript variants have been described. [provided by RefSeq, Nov 2009]

ANO5 Gene-Disease associations (from GenCC):

• gnathodiaphyseal dysplasia

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• autosomal recessive limb-girdle muscular dystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive limb-girdle muscular dystrophy type 2L

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet
• Miyoshi muscular dystrophy 3

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 11-22221210-G-A is Benign according to our data. Variant chr11-22221210-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 197907.
• BP7: Synonymous conserved (PhyloP=2.14 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_213599.3. 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
	ANO5	NM_213599.3	MANE Select	c.294G>A	p.Ala98Ala	splice_region synonymous	Exon 5 of 22	NP_998764.1	Q75V66
	ANO5	NM_001142649.2		c.291G>A	p.Ala97Ala	splice_region synonymous	Exon 5 of 22	NP_001136121.1
	ANO5	NM_001410963.1		c.252G>A	p.Ala84Ala	splice_region synonymous	Exon 4 of 21	NP_001397892.1	A0A804HL91

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANO5	ENST00000324559.9	TSL:1 MANE Select	c.294G>A	p.Ala98Ala	splice_region synonymous	Exon 5 of 22	ENSP00000315371.9	Q75V66
	ANO5	ENST00000682266.1		c.-157G>A		splice_region	Exon 3 of 20	ENSP00000507766.1	A0A804HLK6
	ANO5	ENST00000683411.1		c.-157G>A		splice_region	Exon 4 of 21	ENSP00000508397.1	A0A804HLK6

Frequencies

GnomAD3 genomes AF: 0.000612 AC: 93 AN: 151910 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000789

Gnomad ASJ AF: 0.00577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000810

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000690 AC: 172 AN: 249194 AF XY: 0.000779

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000525

Gnomad ASJ exome AF: 0.00548

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000186

Gnomad NFE exome AF: 0.000801

Gnomad OTH exome AF: 0.000825

GnomAD4 exome AF: 0.000684 AC: 986 AN: 1440814 Hom.: 0 Cov.: 28 AF XY: 0.000709 AC XY: 509 AN XY: 717852

African (AFR) AF: 0.00 AC: 0 AN: 32888

American (AMR) AF: 0.000495 AC: 22 AN: 44478

Ashkenazi Jewish (ASJ) AF: 0.00560 AC: 145 AN: 25912

East Asian (EAS) AF: 0.00 AC: 0 AN: 39396

South Asian (SAS) AF: 0.0000233 AC: 2 AN: 85768

European-Finnish (FIN) AF: 0.000451 AC: 24 AN: 53210

Middle Eastern (MID) AF: 0.000700 AC: 4 AN: 5712

European-Non Finnish (NFE) AF: 0.000677 AC: 740 AN: 1093828

Other (OTH) AF: 0.000822 AC: 49 AN: 59622

GnomAD4 genome AF: 0.000612 AC: 93 AN: 151910 Hom.: 0 Cov.: 32 AF XY: 0.000661 AC XY: 49 AN XY: 74176

African (AFR) AF: 0.000121 AC: 5 AN: 41408

American (AMR) AF: 0.000789 AC: 12 AN: 15206

Ashkenazi Jewish (ASJ) AF: 0.00577 AC: 20 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000810 AC: 55 AN: 67904

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.000933 Hom.: 0

Bravo AF: 0.000710

EpiCase AF: 0.000656

EpiControl AF: 0.00113

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	2	not provided (5)
-	1	-	ANO5-Related Muscle Diseases (1)
-	-	1	Gnathodiaphyseal dysplasia;C1969785:Autosomal recessive limb-girdle muscular dystrophy type 2L (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	15
DANN	Benign	0.84
PhyloP100		2.1
Mutation Taster		=70/30	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.19
dbscSNV1_RF	Benign	0.51
SpliceAI score (max)		0.060		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: rs142858990; hg19: chr11-22242756; COSMIC: COSV100202281;