11-22279669-C-G

Variant names:

• chr11-22279669-C-G
• rs34969327
• NM_213599.3:c.2646C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_213599.3(ANO5):​c.2646C>G​(p.Asn882Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00181 in 1,612,758 control chromosomes in the GnomAD database, including 56 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 Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. N882N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.010 (36 hom., cov: 32)
  • Exomes 𝑓: 0.00095 (20 hom.)
• Consequence: ANO5 NM_213599.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13 O:1
• Conservation: PhyloP100: -0.286
• Publications: 8 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004618734).
• BP6: Variant 11-22279669-C-G is Benign according to our data. Variant chr11-22279669-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128390.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 = 0.0101 (1530/151830) while in subpopulation AFR AF = 0.0352 (1461/41464). AF 95% confidence interval is 0.0337. There are 36 homozygotes in GnomAd4. There are 704 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 36 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.2646C>G	p.Asn882Lys	missense	Exon 22 of 22	NP_998764.1	Q75V66
	ANO5	NM_001142649.2		c.2643C>G	p.Asn881Lys	missense	Exon 22 of 22	NP_001136121.1
	ANO5	NM_001410963.1		c.2604C>G	p.Asn868Lys	missense	Exon 21 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.2646C>G	p.Asn882Lys	missense	Exon 22 of 22	ENSP00000315371.9	Q75V66
	ANO5	ENST00000682341.1		c.2604C>G	p.Asn868Lys	missense	Exon 21 of 21	ENSP00000508251.1	A0A804HL91
	ANO5	ENST00000684663.1		c.2601C>G	p.Asn867Lys	missense	Exon 21 of 21	ENSP00000508009.1	A0A804HKP2

Frequencies

GnomAD3 genomes AF: 0.0101 AC: 1531 AN: 151714 Hom.: 36 Cov.: 32

Gnomad AFR AF: 0.0353

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00335

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000590

Gnomad OTH AF: 0.00719

GnomAD2 exomes AF: 0.00251 AC: 631 AN: 250920 AF XY: 0.00170

Gnomad AFR exome AF: 0.0346

Gnomad AMR exome AF: 0.00168

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000441

Gnomad OTH exome AF: 0.000981

GnomAD4 exome AF: 0.000949 AC: 1387 AN: 1460928 Hom.: 20 Cov.: 32 AF XY: 0.000772 AC XY: 561 AN XY: 726722

African (AFR) AF: 0.0344 AC: 1149 AN: 33448

American (AMR) AF: 0.00191 AC: 85 AN: 44616

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86236

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

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5758

European-Non Finnish (NFE) AF: 0.0000369 AC: 41 AN: 1111362

Other (OTH) AF: 0.00172 AC: 104 AN: 60350

GnomAD4 genome AF: 0.0101 AC: 1530 AN: 151830 Hom.: 36 Cov.: 32 AF XY: 0.00948 AC XY: 704 AN XY: 74234

African (AFR) AF: 0.0352 AC: 1461 AN: 41464

American (AMR) AF: 0.00328 AC: 50 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

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

European-Non Finnish (NFE) AF: 0.0000590 AC: 4 AN: 67774

Other (OTH) AF: 0.00712 AC: 15 AN: 2108

Alfa AF: 0.000517 Hom.: 0

Bravo AF: 0.0115

ESP6500AA AF: 0.0386 AC: 170

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00315 AC: 383

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (4)
-	-	2	Gnathodiaphyseal dysplasia (2)
-	-	1	ANO5-Related Muscle Diseases (1)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2L (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	0.11
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	8.0
DANN	Benign	0.87
DEOGEN2	Benign	0.034	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.60	T
MetaRNN	Benign	0.0046	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L
PhyloP100		-0.29
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.13
Sift	Benign	0.70	T
Sift4G	Benign	0.77	T
Polyphen		0.10	B
Vest4		0.64
MutPred		0.14		Gain of ubiquitination at N882 (P = 0.0289)
MVP		0.17
MPC		0.099
ClinPred		0.0059	T
GERP RS		-4.8
Varity_R		0.061
gMVP		0.40
Mutation Taster		=90/10	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: rs34969327; hg19: chr11-22301215;