chr11-22193232-A-C

Variant names:

• chr11-22193232-A-C
• rs114897158
• NM_213599.3:c.-261A>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_213599.3(ANO5):​c.-261A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00242 in 1,098,944 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.012 (26 hom., cov: 31)
  • Exomes 𝑓: 0.0011 (14 hom.)
• Consequence: ANO5 NM_213599.3 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: -1.07
• 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 11-22193232-A-C is Benign according to our data. Variant chr11-22193232-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 304089.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0116 (1570/135380) while in subpopulation AFR AF = 0.0411 (1483/36096). AF 95% confidence interval is 0.0393. There are 26 homozygotes in GnomAd4. There are 756 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 26 AR,AD gene

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.-261A>C		5_prime_UTR	Exon 1 of 22	NP_998764.1	Q75V66
	ANO5	NM_001142649.2		c.-261A>C		5_prime_UTR	Exon 1 of 22	NP_001136121.1
	ANO5	NM_001410963.1		c.-261A>C		5_prime_UTR	Exon 1 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.-261A>C		5_prime_UTR	Exon 1 of 22	ENSP00000315371.9	Q75V66
	ANO5	ENST00000682341.1		c.-261A>C		5_prime_UTR	Exon 1 of 21	ENSP00000508251.1	A0A804HL91
	ANO5	ENST00000684663.1		c.-261A>C		5_prime_UTR	Exon 1 of 21	ENSP00000508009.1	A0A804HKP2

Frequencies

GnomAD3 genomes AF: 0.0115 AC: 1557 AN: 135266 Hom.: 26 Cov.: 31

Gnomad AFR AF: 0.0408

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00465

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000214

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00763

Gnomad NFE AF: 0.0000486

Gnomad OTH AF: 0.00984

GnomAD4 exome AF: 0.00113 AC: 1088 AN: 963564 Hom.: 14 Cov.: 29 AF XY: 0.00106 AC XY: 480 AN XY: 453290

African (AFR) AF: 0.0486 AC: 938 AN: 19312

American (AMR) AF: 0.00407 AC: 33 AN: 8100

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9342

East Asian (EAS) AF: 0.00 AC: 0 AN: 17468

South Asian (SAS) AF: 0.000108 AC: 3 AN: 27832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7868

Middle Eastern (MID) AF: 0.00178 AC: 4 AN: 2252

European-Non Finnish (NFE) AF: 0.0000227 AC: 19 AN: 836524

Other (OTH) AF: 0.00261 AC: 91 AN: 34866

GnomAD4 genome AF: 0.0116 AC: 1570 AN: 135380 Hom.: 26 Cov.: 31 AF XY: 0.0114 AC XY: 756 AN XY: 66038

African (AFR) AF: 0.0411 AC: 1483 AN: 36096

American (AMR) AF: 0.00465 AC: 63 AN: 13562

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3196

East Asian (EAS) AF: 0.000214 AC: 1 AN: 4674

South Asian (SAS) AF: 0.00 AC: 0 AN: 4106

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9148

Middle Eastern (MID) AF: 0.00826 AC: 2 AN: 242

European-Non Finnish (NFE) AF: 0.0000486 AC: 3 AN: 61704

Other (OTH) AF: 0.00971 AC: 18 AN: 1854

Alfa AF: 0.00586 Hom.: 2

Bravo AF: 0.0122

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	ANO5-Related Muscle Diseases (1)
-	1	-	Limb-girdle muscular dystrophy, recessive (1)
-	1	-	Miyoshi myopathy (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.8
DANN	Benign	0.31
PhyloP100		-1.1
PromoterAI		-0.0028	Neutral
Mutation Taster		=300/0	polymorphism

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: rs114897158; hg19: chr11-22214778;