rs141845119

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The c.2836C>T(NM_004999.4) variant in MYO6 is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 946 (p.Arg946Cys). The filtering allele frequency of the c.2836C>T variant in the MYO6 gene is 0.12% for South Asian chromosomes by the Genome Aggregation Database v4 (94/63976 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal dominant hearing loss variants (BA1). (ClinGen Hearing Loss VCEP specifications version 2; 12.18.2024) 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
NM_004999.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:5B:8

Conservation

PhyloP100: 3.13

Publications

8 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: Labcorp Genetics (formerly Invitae), Ambry Genetics
nonsyndromic genetic hearing loss
Inheritance: AD, AR Classification: DEFINITIVE, MODERATE Submitted by: G2P, ClinGen
autosomal recessive nonsyndromic hearing loss 37
Inheritance: AR Classification: STRONG, MODERATE Submitted by: 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 -8 ACMG points.

BA1

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004999.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MYO6	NM_004999.4	MANE Select	c.2836C>T	p.Arg946Cys	missense	Exon 26 of 35	NP_004990.3
MYO6	NM_001368865.1		c.2836C>T	p.Arg946Cys	missense	Exon 26 of 36	NP_001355794.1	A0A590UJ40
MYO6	NM_001368866.1		c.2836C>T	p.Arg946Cys	missense	Exon 26 of 35	NP_001355795.1	A0A1Y0BRN3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MYO6	ENST00000369977.8	TSL:1 MANE Select	c.2836C>T	p.Arg946Cys	missense	Exon 26 of 35	ENSP00000358994.3	Q9UM54-1
MYO6	ENST00000615563.4	TSL:1	c.2836C>T	p.Arg946Cys	missense	Exon 25 of 32	ENSP00000478013.1	Q9UM54-2
MYO6	ENST00000664640.1		c.2836C>T	p.Arg946Cys	missense	Exon 26 of 36	ENSP00000499278.1	A0A590UJ40

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

GnomAD2 exomes

AF:

0.000733

AC:

184

AN:

250866

AF XY:

0.000832

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 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

African (AFR)

AF:

0.000120

AC:

AN:

33424

American (AMR)

AF:

0.0000671

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.000115

AC:

AN:

26118

East Asian (EAS)

AF:

0.00

AC:

AN:

39678

South Asian (SAS)

AF:

0.00122

AC:

105

AN:

86220

European-Finnish (FIN)

AF:

0.00165

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.000421

AC:

468

AN:

1110644

Other (OTH)

AF:

0.000646

AC:

AN:

60328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

113

150

188

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000427

AC:

AN:

152060

Hom.:

Cov.:

AF XY:

0.000525

AC XY:

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.0000965

AC:

AN:

41466

American (AMR)

AF:

0.0000655

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00208

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.000568

AC:

AN:

10562

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.000632

AC:

AN:

67988

Other (OTH)

AF:

0.00

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000596

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

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (7)

not specified (2)

Autosomal dominant nonsyndromic hearing loss 22 (1)

Autosomal recessive nonsyndromic hearing loss 37 (1)

MYO6-related disorder (1)

Nonsyndromic genetic hearing loss (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.33

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.50

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.022

MetaRNN

Benign

0.036

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.6

PhyloP100

3.1

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-4.5

REVEL

Benign

0.16

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.011

Polyphen

0.99

Vest4

0.85

MVP

0.61

MPC

0.37

ClinPred

0.085

GERP RS

6.0

PromoterAI

-0.043

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.38

Mutation Taster

=89/11

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over