6-75890234-C-T

Position:

chr6-75890234-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS1

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency of the p.Arg946Cys variant in the MYO6 gene is 0.095% (39/30776) of South Asian chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal dominant hearing loss (BS1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA177354/MONDO:0019497/005

Frequency

Genomes: 𝑓 0.00043 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00049 ( 1 hom. )

Consequence

MYO6
ENST00000369977.8 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:5B:7

Conservation

PhyloP100: 3.13

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO6	NM_004999.4 linkuse as main transcript	c.2836C>T	p.Arg946Cys	missense_variant	26/35	ENST00000369977.8	NP_004990.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO6	ENST00000369977.8 linkuse as main transcript	c.2836C>T	p.Arg946Cys	missense_variant	26/35	1	NM_004999.4	ENSP00000358994	A1	Q9UM54-1

Frequencies

GnomAD3 genomes

AF:

0.000428

AC:

AN:

151946

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000967

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00208

Gnomad FIN

AF:

0.000568

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000632

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000733

AC:

184

AN:

250866

Hom.:

AF XY:

0.000832

AC XY:

113

AN XY:

135756

show subpopulations

Gnomad AFR exome

AF:

0.0000620

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00127

Gnomad FIN exome

AF:

0.00111

Gnomad NFE exome

AF:

0.000944

Gnomad OTH exome

AF:

0.00131

GnomAD4 exome

AF:

0.000487

AC:

711

AN:

1460296

Hom.:

Cov.:

AF XY:

0.000541

AC XY:

393

AN XY:

726562

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00122

Gnomad4 FIN exome

AF:

0.00165

Gnomad4 NFE exome

AF:

0.000421

Gnomad4 OTH exome

AF:

0.000646

GnomAD4 genome

AF:

0.000427

AC:

AN:

152060

Hom.:

Cov.:

AF XY:

0.000525

AC XY:

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00208

Gnomad4 FIN

AF:

0.000568

Gnomad4 NFE

AF:

0.000632

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000598

Hom.:

Bravo

AF:

0.000242

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000906

AC:

110

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000436

EpiControl

AF:

0.000296

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:5Benign:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 30, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 21, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 20, 2020	This variant is associated with the following publications: (PMID: 27068579) -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 20, 2023	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 16, 2013

The Arg946Cys variant in MYO6 has not been reported in individuals with hearing loss, but has been identified in 0.04% (4/8600) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs141845119). Although this variant has been seen in the general population, it s frequency is not high enough to rule out a pathogenic role. Computational anal yses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. In summary, the clinical significance of this variant cannot be determined with ce rtainty. -

Autosomal recessive nonsyndromic hearing loss 37

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Nonsyndromic genetic hearing loss

Benign:1

Likely benign, reviewed by expert panel

curation

ClinGen Hearing Loss Variant Curation Expert Panel

Sep 28, 2018

The filtering allele frequency of the p.Arg946Cys variant in the MYO6 gene is 0.095% (39/30776) of South Asian chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal dominant hearing loss (BS1). -

Autosomal dominant nonsyndromic hearing loss 22

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

MYO6-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 29, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.33

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.50

T;.;.;.;D;D;.

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.92

D;.;D;D;D;D;T

M_CAP

Benign

0.022

MetaRNN

Benign

0.036

T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.6

.;M;M;M;.;.;.

MutationTaster

Benign

0.99

D;D;D;D

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-4.5

D;D;D;.;D;.;D

REVEL

Benign

0.16

Sift

Uncertain

0.0010

D;D;D;.;D;.;D

Sift4G

Uncertain

0.011

D;D;D;D;D;D;D

Polyphen

0.99

.;D;D;D;.;.;.

Vest4

0.85

MVP

0.61

MPC

0.37

ClinPred

0.085

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.38

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over