rs11756446

Variant names:

• chr6-75866573-C-T
• rs11756446
• NM_004999.4:c.1722C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004999.4(MYO6):​c.1722C>T​(p.Asp574Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0566 in 1,613,280 control chromosomes in the GnomAD database, including 2,942 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.043 (211 hom., cov: 32)
  • Exomes 𝑓: 0.058 (2731 hom.)
• Consequence: MYO6 NM_004999.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -2.40
• Publications: 7 publications found

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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 6-75866573-C-T is Benign according to our data. Variant chr6-75866573-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 45140.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.4 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0578 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO6	NM_004999.4	c.1722C>T	p.Asp574Asp	synonymous_variant	Exon 17 of 35	ENST00000369977.8	NP_004990.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO6	ENST00000369977.8	c.1722C>T	p.Asp574Asp	synonymous_variant	Exon 17 of 35	1	NM_004999.4	ENSP00000358994.3

Frequencies

GnomAD3 genomes AF: 0.0429 AC: 6527 AN: 152040 Hom.: 211 Cov.: 32

Gnomad AFR AF: 0.0107

Gnomad AMI AF: 0.204

Gnomad AMR AF: 0.0329

Gnomad ASJ AF: 0.0729

Gnomad EAS AF: 0.0142

Gnomad SAS AF: 0.0587

Gnomad FIN AF: 0.0612

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0593

Gnomad OTH AF: 0.0430

GnomAD2 exomes AF: 0.0509 AC: 12806 AN: 251428 AF XY: 0.0538

Gnomad AFR exome AF: 0.00935

Gnomad AMR exome AF: 0.0248

Gnomad ASJ exome AF: 0.0713

Gnomad EAS exome AF: 0.0192

Gnomad FIN exome AF: 0.0642

Gnomad NFE exome AF: 0.0613

Gnomad OTH exome AF: 0.0551

GnomAD4 exome AF: 0.0580 AC: 84709 AN: 1461124 Hom.: 2731 Cov.: 31 AF XY: 0.0585 AC XY: 42558 AN XY: 726882

African (AFR) AF: 0.00863 AC: 289 AN: 33474

American (AMR) AF: 0.0259 AC: 1158 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0690 AC: 1803 AN: 26128

East Asian (EAS) AF: 0.0115 AC: 455 AN: 39684

South Asian (SAS) AF: 0.0655 AC: 5646 AN: 86238

European-Finnish (FIN) AF: 0.0637 AC: 3401 AN: 53412

Middle Eastern (MID) AF: 0.0640 AC: 369 AN: 5768

European-Non Finnish (NFE) AF: 0.0613 AC: 68132 AN: 1111350

Other (OTH) AF: 0.0573 AC: 3456 AN: 60350

GnomAD4 genome AF: 0.0429 AC: 6530 AN: 152156 Hom.: 211 Cov.: 32 AF XY: 0.0433 AC XY: 3218 AN XY: 74378

African (AFR) AF: 0.0107 AC: 444 AN: 41504

American (AMR) AF: 0.0329 AC: 502 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0729 AC: 253 AN: 3472

East Asian (EAS) AF: 0.0145 AC: 75 AN: 5190

South Asian (SAS) AF: 0.0591 AC: 285 AN: 4820

European-Finnish (FIN) AF: 0.0612 AC: 646 AN: 10564

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0593 AC: 4036 AN: 68008

Other (OTH) AF: 0.0436 AC: 92 AN: 2112

Alfa AF: 0.0550 Hom.: 207

Bravo AF: 0.0395

Asia WGS AF: 0.0420 AC: 144 AN: 3478

EpiCase AF: 0.0561

EpiControl AF: 0.0602

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Aug 16, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 19, 2009

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

Nov 28, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Autosomal recessive nonsyndromic hearing loss 37 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

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

Autosomal dominant nonsyndromic hearing loss 22 Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.32
DANN	Benign	0.83
PhyloP100		-2.4
Mutation Taster		=96/4	polymorphism (auto)

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: rs11756446; hg19: chr6-76576290;