rs138144479

Variant names:

• chr11-22239606-C-G
• rs138144479
• NM_213599.3:c.800C>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_213599.3(ANO5):​c.800C>G​(p.Thr267Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00124 in 1,612,896 control chromosomes in the GnomAD database, including 17 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.0067 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00068 (9 hom.)
• Consequence: ANO5 NM_213599.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.442
• Publications: 7 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):

• autosomal recessive limb-girdle muscular dystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• gnathodiaphyseal dysplasia

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
• autosomal recessive limb-girdle muscular dystrophy type 2L

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

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

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_213599.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.010611832).
• BP6: Variant 11-22239606-C-G is Benign according to our data. Variant chr11-22239606-C-G is described in ClinVar as Benign. ClinVar VariationId is 226458.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00668 (1017/152134) while in subpopulation AFR AF = 0.0232 (962/41518). AF 95% confidence interval is 0.022. There are 8 homozygotes in GnomAd4. There are 480 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 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.800C>G	p.Thr267Ser	missense	Exon 9 of 22	NP_998764.1
	ANO5	NM_001142649.2		c.797C>G	p.Thr266Ser	missense	Exon 9 of 22	NP_001136121.1
	ANO5	NM_001410963.1		c.758C>G	p.Thr253Ser	missense	Exon 8 of 21	NP_001397892.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANO5	ENST00000324559.9	TSL:1 MANE Select	c.800C>G	p.Thr267Ser	missense	Exon 9 of 22	ENSP00000315371.9
	ANO5	ENST00000682341.1		c.758C>G	p.Thr253Ser	missense	Exon 8 of 21	ENSP00000508251.1
	ANO5	ENST00000684663.1		c.755C>G	p.Thr252Ser	missense	Exon 8 of 21	ENSP00000508009.1

Frequencies

GnomAD3 genomes AF: 0.00660 AC: 1004 AN: 152016 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0229

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00170 AC: 428 AN: 251188 AF XY: 0.00122

Gnomad AFR exome AF: 0.0224

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.000979

GnomAD4 exome AF: 0.000676 AC: 987 AN: 1460762 Hom.: 9 Cov.: 30 AF XY: 0.000607 AC XY: 441 AN XY: 726690

African (AFR) AF: 0.0237 AC: 791 AN: 33424

American (AMR) AF: 0.00139 AC: 62 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39614

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00122 AC: 7 AN: 5760

European-Non Finnish (NFE) AF: 0.0000234 AC: 26 AN: 1111192

Other (OTH) AF: 0.00159 AC: 96 AN: 60342

GnomAD4 genome AF: 0.00668 AC: 1017 AN: 152134 Hom.: 8 Cov.: 32 AF XY: 0.00645 AC XY: 480 AN XY: 74372

African (AFR) AF: 0.0232 AC: 962 AN: 41518

American (AMR) AF: 0.00262 AC: 40 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67954

Other (OTH) AF: 0.00568 AC: 12 AN: 2112

Alfa AF: 0.00112 Hom.: 0

Bravo AF: 0.00803

ESP6500AA AF: 0.0207 AC: 91

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00199 AC: 242

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	5.0
DANN	Benign	0.60
DEOGEN2	Benign	0.039	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.23	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.44
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.55	N
REVEL	Benign	0.037
Sift	Benign	0.67	T
Sift4G	Benign	0.71	T
Polyphen		0.087	B
Vest4		0.70
MutPred		0.23		Gain of glycosylation at T267 (P = 0.0608)
MVP		0.22
MPC		0.086
ClinPred		0.00089	T
GERP RS		-2.5
Varity_R		0.048
gMVP		0.31
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs138144479; hg19: chr11-22261152; COSMIC: COSV61086440;