11-22274548-CTTTTT-CTTTTTTT

Variant names:

• chr11-22274548-C-CTT
• rs72105710
• NM_213599.3:c.2236-11_2236-10dupTT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_213599.3(ANO5):​c.2236-11_2236-10dupTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000339 in 1,266,118 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., cov: 27)
  • Exomes 𝑓: 0.00035 (0 hom.)
• Consequence: ANO5 NM_213599.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• 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):

• 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 -8 ACMG points.

• BP6: Variant 11-22274548-C-CTT is Benign according to our data. Variant chr11-22274548-C-CTT is described in ClinVar as [Benign]. Clinvar id is 592736.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANO5	NM_213599.3	c.2236-11_2236-10dupTT		intron_variant	Intron 19 of 21	ENST00000324559.9	NP_998764.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANO5	ENST00000324559.9	c.2236-21_2236-20insTT		intron_variant	Intron 19 of 21	1	NM_213599.3	ENSP00000315371.9

Frequencies

GnomAD3 genomes AF: 0.000231 AC: 34 AN: 147070 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.0000744

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000314

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000422

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000304 AC: 35 AN: 115060 AF XY: 0.000371

Gnomad AFR exome AF: 0.000296

Gnomad AMR exome AF: 0.0000861

Gnomad ASJ exome AF: 0.000309

Gnomad EAS exome AF: 0.000155

Gnomad FIN exome AF: 0.000292

Gnomad NFE exome AF: 0.000403

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000353 AC: 395 AN: 1119048 Hom.: 0 Cov.: 0 AF XY: 0.000353 AC XY: 195 AN XY: 552904

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

African (AFR) AF: 0.000116 AC: 3 AN: 25820

American (AMR) AF: 0.000109 AC: 3 AN: 27466

Ashkenazi Jewish (ASJ) AF: 0.0000547 AC: 1 AN: 18286

East Asian (EAS) AF: 0.000105 AC: 3 AN: 28538

South Asian (SAS) AF: 0.0000647 AC: 4 AN: 61840

European-Finnish (FIN) AF: 0.000173 AC: 7 AN: 40416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4640

European-Non Finnish (NFE) AF: 0.000409 AC: 354 AN: 865836

Other (OTH) AF: 0.000433 AC: 20 AN: 46206

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000231 AC: 34 AN: 147070 Hom.: 0 Cov.: 27 AF XY: 0.000321 AC XY: 23 AN XY: 71620

African (AFR) AF: 0.0000744 AC: 3 AN: 40300

American (AMR) AF: 0.00 AC: 0 AN: 14650

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3368

East Asian (EAS) AF: 0.00 AC: 0 AN: 5064

South Asian (SAS) AF: 0.00 AC: 0 AN: 4644

European-Finnish (FIN) AF: 0.000314 AC: 3 AN: 9544

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.000422 AC: 28 AN: 66284

Other (OTH) AF: 0.00 AC: 0 AN: 2004

Alfa AF: 0.00 Hom.: 12

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

May 08, 2018

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Gnathodiaphyseal dysplasia;C1969785:Autosomal recessive limb-girdle muscular dystrophy type 2L Benign:1

May 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.69

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs72105710; hg19: chr11-22296094;