NM_213599.3:c.2236-10dupT

Variant names:

• chr11-22274548-C-CT
• rs72105710
• NM_213599.3:c.2236-10dupT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_213599.3(ANO5):​c.2236-10dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0194 in 1,154,642 control chromosomes in the GnomAD database, including 16 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0076 (10 hom., cov: 27)
  • Exomes 𝑓: 0.021 (6 hom.)
• Consequence: ANO5 NM_213599.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.693
• 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 -16 ACMG points.

• BP6: Variant 11-22274548-C-CT is Benign according to our data. Variant chr11-22274548-C-CT is described in ClinVar as Benign. ClinVar VariationId is 195544.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 = 0.0076 (1118/147054) while in subpopulation AFR AF = 0.0223 (901/40388). AF 95% confidence interval is 0.0211. There are 10 homozygotes in GnomAd4. There are 506 alleles in the male GnomAd4 subpopulation. Median coverage is 27. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 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.2236-10dupT		intron	N/A	NP_998764.1	Q75V66
	ANO5	NM_001142649.2		c.2233-10dupT		intron	N/A	NP_001136121.1
	ANO5	NM_001410963.1		c.2194-10dupT		intron	N/A	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.2236-21_2236-20insT		intron	N/A	ENSP00000315371.9	Q75V66
	ANO5	ENST00000682341.1		c.2194-21_2194-20insT		intron	N/A	ENSP00000508251.1	A0A804HL91
	ANO5	ENST00000684663.1		c.2191-21_2191-20insT		intron	N/A	ENSP00000508009.1	A0A804HKP2

Frequencies

GnomAD3 genomes AF: 0.00758 AC: 1114 AN: 146982 Hom.: 10 Cov.: 27

Gnomad AFR AF: 0.0222

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00458

Gnomad ASJ AF: 0.00208

Gnomad EAS AF: 0.0164

Gnomad SAS AF: 0.000431

Gnomad FIN AF: 0.000945

Gnomad MID AF: 0.00968

Gnomad NFE AF: 0.000574

Gnomad OTH AF: 0.00450

GnomAD2 exomes AF: 0.0304 AC: 3497 AN: 115060 AF XY: 0.0295

Gnomad AFR exome AF: 0.0461

Gnomad AMR exome AF: 0.0532

Gnomad ASJ exome AF: 0.0457

Gnomad EAS exome AF: 0.0872

Gnomad FIN exome AF: 0.0214

Gnomad NFE exome AF: 0.0170

Gnomad OTH exome AF: 0.0373

GnomAD4 exome AF: 0.0211 AC: 21236 AN: 1007588 Hom.: 6 Cov.: 0 AF XY: 0.0210 AC XY: 10468 AN XY: 498356

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0455 AC: 1072 AN: 23556

American (AMR) AF: 0.0328 AC: 821 AN: 25008

Ashkenazi Jewish (ASJ) AF: 0.0297 AC: 480 AN: 16178

East Asian (EAS) AF: 0.0481 AC: 1138 AN: 23652

South Asian (SAS) AF: 0.0316 AC: 1792 AN: 56792

European-Finnish (FIN) AF: 0.0189 AC: 708 AN: 37442

Middle Eastern (MID) AF: 0.0313 AC: 135 AN: 4316

European-Non Finnish (NFE) AF: 0.0181 AC: 14121 AN: 779110

Other (OTH) AF: 0.0233 AC: 969 AN: 41534

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00760 AC: 1118 AN: 147054 Hom.: 10 Cov.: 27 AF XY: 0.00706 AC XY: 506 AN XY: 71654

African (AFR) AF: 0.0223 AC: 901 AN: 40388

American (AMR) AF: 0.00450 AC: 66 AN: 14658

Ashkenazi Jewish (ASJ) AF: 0.00208 AC: 7 AN: 3364

East Asian (EAS) AF: 0.0164 AC: 83 AN: 5050

South Asian (SAS) AF: 0.000432 AC: 2 AN: 4634

European-Finnish (FIN) AF: 0.000945 AC: 9 AN: 9520

Middle Eastern (MID) AF: 0.0105 AC: 3 AN: 286

European-Non Finnish (NFE) AF: 0.000574 AC: 38 AN: 66238

Other (OTH) AF: 0.00447 AC: 9 AN: 2014

Alfa AF: 0.00575 Hom.: 12

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	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
PhyloP100		0.69
Mutation Taster		=100/0	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: rs72105710; hg19: chr11-22296094;