rs55662069

Variant names:

• chr6-75886870-C-T
• rs55662069
• NM_004999.4:c.2534C>T
• MYO6 p.Thr845Ile

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_004999.4(MYO6):​c.2534C>T​(p.Thr845Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0042 in 1,613,346 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene MYO6 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0031 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0043 (15 hom.)
• Consequence: MYO6 NM_004999.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: 3.82
• Publications: 8 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)
• nonsyndromic genetic hearing loss

  Inheritance: AR, AD Classification: DEFINITIVE, MODERATE Submitted by: G2P, ClinGen
• autosomal recessive nonsyndromic hearing loss 37

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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

Specifications for MYO6 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011608064).
• BP6: Variant 6-75886870-C-T is Benign according to our data. Variant chr6-75886870-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45144.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00305 (464/152104) while in subpopulation NFE AF = 0.00547 (372/67996). AF 95% confidence interval is 0.00501. There are 0 homozygotes in GnomAd4. There are 224 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 15 AD,AR gene

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.2534C>T	p.Thr845Ile	missense	Exon 25 of 35	NP_004990.3
	MYO6	NM_001368865.1		c.2534C>T	p.Thr845Ile	missense	Exon 25 of 36	NP_001355794.1	A0A590UJ40
	MYO6	NM_001368866.1		c.2534C>T	p.Thr845Ile	missense	Exon 25 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.2534C>T	p.Thr845Ile	missense	Exon 25 of 35	ENSP00000358994.3	Q9UM54-1
	MYO6	ENST00000615563.4	TSL:1	c.2534C>T	p.Thr845Ile	missense	Exon 24 of 32	ENSP00000478013.1	Q9UM54-2
	MYO6	ENST00000664640.1		c.2534C>T	p.Thr845Ile	missense	Exon 25 of 36	ENSP00000499278.1	A0A590UJ40

Frequencies

GnomAD3 genomes AF: 0.00305 AC: 464 AN: 151986 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000943

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000947

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00547

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00256 AC: 644 AN: 251344 AF XY: 0.00231

Gnomad AFR exome AF: 0.000739

Gnomad AMR exome AF: 0.00139

Gnomad ASJ exome AF: 0.00437

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000324

Gnomad NFE exome AF: 0.00457

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00432 AC: 6317 AN: 1461242 Hom.: 15 Cov.: 31 AF XY: 0.00412 AC XY: 2997 AN XY: 726956

African (AFR) AF: 0.000628 AC: 21 AN: 33456

American (AMR) AF: 0.00159 AC: 71 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00440 AC: 115 AN: 26124

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39610

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86252

European-Finnish (FIN) AF: 0.000412 AC: 22 AN: 53360

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5760

European-Non Finnish (NFE) AF: 0.00529 AC: 5884 AN: 1111598

Other (OTH) AF: 0.00331 AC: 200 AN: 60366

GnomAD4 genome AF: 0.00305 AC: 464 AN: 152104 Hom.: 0 Cov.: 32 AF XY: 0.00301 AC XY: 224 AN XY: 74354

African (AFR) AF: 0.000940 AC: 39 AN: 41476

American (AMR) AF: 0.00157 AC: 24 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00519 AC: 18 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.0000947 AC: 1 AN: 10558

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00547 AC: 372 AN: 67996

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00449 Hom.: 8

Bravo AF: 0.00304

Asia WGS AF: 0.000289 AC: 1 AN: 3476

EpiCase AF: 0.00513

EpiControl AF: 0.00409

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	2	not specified (2)
-	-	1	Autosomal dominant nonsyndromic hearing loss 22 (1)
-	1	-	Autosomal recessive nonsyndromic hearing loss 37 (1)
-	-	1	MYO6-related disorder (1)
-	-	1	Obesity (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.10
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.012	T
MetaSVM	Uncertain	0.39	D
MutationAssessor	Benign	1.7	L
PhyloP100		3.8
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.48
Sift	Benign	0.039	D
Sift4G	Uncertain	0.056	T
gMVP		0.52
Mutation Taster		=99/1	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs55662069;

hg19: chr6-76596587;

COSMIC: COSV99067544;

COSMIC: COSV99067544;