rs12606

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004999.4(MYO6):c.*12C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.301 in 1,605,022 control chromosomes in the GnomAD database, including 78,954 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.23 ( 5144 hom., cov: 32)

Exomes 𝑓: 0.31 ( 73810 hom. )

Consequence

MYO6
NM_004999.4 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.0710

Publications

14 publications found

Variant links:

Genes affected

MYO6 (HGNC:7605): (myosin VI) This gene encodes a reverse-direction motor protein that moves toward the minus end of actin filaments and plays a role in intracellular vesicle and organelle transport. The protein consists of a motor domain containing an ATP- and an actin-binding site and a globular tail which interacts with other proteins. This protein maintains the structural integrity of inner ear hair cells and mutations in this gene cause non-syndromic autosomal dominant and recessive hearing loss. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2014]

MYO6 Gene-Disease associations (from GenCC):

autosomal dominant nonsyndromic hearing loss 22
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia
nonsyndromic genetic hearing loss
Inheritance: AD, AR Classification: DEFINITIVE, MODERATE Submitted by: ClinGen, G2P
autosomal recessive nonsyndromic hearing loss 37
Inheritance: AR Classification: STRONG, MODERATE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
autosomal dominant nonsyndromic hearing loss
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
progressive sensorineural hearing loss-hypertrophic cardiomyopathy syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

MYO6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 6-75915024-C-T is Benign according to our data. Variant chr6-75915024-C-T is described in ClinVar as Benign. ClinVar VariationId is 45130.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.332 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO6	NM_004999.4 link	c.*12C>T		3_prime_UTR_variant	Exon 35 of 35	ENST00000369977.8	NP_004990.3	Q9UM54-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO6	ENST00000369977.8 link	c.*12C>T		3_prime_UTR_variant	Exon 35 of 35	1	NM_004999.4	ENSP00000358994.3		Q9UM54-1

Frequencies

GnomAD3 genomes

AF:

0.227

AC:

34529

AN:

152028

Hom.:

5147

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0584

Gnomad AMI

AF:

0.316

Gnomad AMR

AF:

0.206

Gnomad ASJ

AF:

0.312

Gnomad EAS

AF:

0.0522

Gnomad SAS

AF:

0.257

Gnomad FIN

AF:

0.254

Gnomad MID

AF:

0.399

Gnomad NFE

AF:

0.335

Gnomad OTH

AF:

0.228

GnomAD2 exomes

AF:

0.250

AC:

59988

AN:

239502

AF XY:

0.263

show subpopulations

Gnomad AFR exome

AF:

0.0513

Gnomad AMR exome

AF:

0.143

Gnomad ASJ exome

AF:

0.308

Gnomad EAS exome

AF:

0.0505

Gnomad FIN exome

AF:

0.247

Gnomad NFE exome

AF:

0.333

Gnomad OTH exome

AF:

0.282

GnomAD4 exome

AF:

0.309

AC:

449403

AN:

1452876

Hom.:

73810

Cov.:

AF XY:

0.310

AC XY:

223868

AN XY:

722106

show subpopulations

African (AFR)

AF:

0.0516

AC:

1719

AN:

33324

American (AMR)

AF:

0.152

AC:

6629

AN:

43752

Ashkenazi Jewish (ASJ)

AF:

0.308

AC:

7997

AN:

25978

East Asian (EAS)

AF:

0.0491

AC:

1938

AN:

39496

South Asian (SAS)

AF:

0.271

AC:

23076

AN:

85258

European-Finnish (FIN)

AF:

0.248

AC:

13140

AN:

52902

Middle Eastern (MID)

AF:

0.384

AC:

1753

AN:

4564

European-Non Finnish (NFE)

AF:

0.340

AC:

376152

AN:

1107604

Other (OTH)

AF:

0.283

AC:

16999

AN:

59998

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

14160

28319

42479

56638

70798

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11784

23568

35352

47136

58920

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.227

AC:

34509

AN:

152146

Hom.:

5144

Cov.:

AF XY:

0.223

AC XY:

16556

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.0583

AC:

2421

AN:

41534

American (AMR)

AF:

0.205

AC:

3141

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.312

AC:

1083

AN:

3470

East Asian (EAS)

AF:

0.0525

AC:

272

AN:

5182

South Asian (SAS)

AF:

0.256

AC:

1234

AN:

4820

European-Finnish (FIN)

AF:

0.254

AC:

2683

AN:

10556

Middle Eastern (MID)

AF:

0.384

AC:

113

AN:

294

European-Non Finnish (NFE)

AF:

0.335

AC:

22799

AN:

67980

Other (OTH)

AF:

0.225

AC:

475

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1268

2536

3805

5073

6341

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

364

728

1092

1456

1820

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.303

Hom.:

5156

Bravo

AF:

0.213

Asia WGS

AF:

0.141

AC:

496

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Apr 17, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 37

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal dominant nonsyndromic hearing loss 22

Benign:2

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:1

Aug 03, 2017

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.37

(source)

DANN

Benign

0.34

PhyloP100

-0.071

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over