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: 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

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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO6	NM_004999.4	MANE Select	c.1722C>T	p.Asp574Asp	synonymous	Exon 17 of 35	NP_004990.3
	MYO6	NM_001368865.1		c.1722C>T	p.Asp574Asp	synonymous	Exon 17 of 36	NP_001355794.1	A0A590UJ40
	MYO6	NM_001368866.1		c.1722C>T	p.Asp574Asp	synonymous	Exon 17 of 35	NP_001355795.1	A0A1Y0BRN3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO6	ENST00000369977.8	TSL:1 MANE Select	c.1722C>T	p.Asp574Asp	synonymous	Exon 17 of 35	ENSP00000358994.3	Q9UM54-1
	MYO6	ENST00000615563.4	TSL:1	c.1722C>T	p.Asp574Asp	synonymous	Exon 16 of 32	ENSP00000478013.1	Q9UM54-2
	MYO6	ENST00000664640.1		c.1722C>T	p.Asp574Asp	synonymous	Exon 17 of 36	ENSP00000499278.1	A0A590UJ40

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Autosomal dominant nonsyndromic hearing loss 22 (1)
-	-	1	Autosomal recessive nonsyndromic hearing loss 37 (1)

Computational scores

Source: dbNSFP v4.9

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;