rs146461956

Variant names:

• chr6-75914978-A-G
• rs146461956
• NM_004999.4:c.3824A>G

Your query was ambiguous. Multiple possible variants found:

• chr6-75914978-A-G
• chr6-75914978-A-T

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.3824A>G​(p.Tyr1275Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00209 in 1,613,628 control chromosomes in the GnomAD database, including 46 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 0.0035 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (40 hom.)
• Consequence: MYO6 NM_004999.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 7.11
• Publications: 9 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

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=0.009372115).
• BP6: Variant 6-75914978-A-G is Benign according to our data. Variant chr6-75914978-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45160.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00347 (529/152286) while in subpopulation AMR AF = 0.0102 (156/15294). AF 95% confidence interval is 0.00889. There are 6 homozygotes in GnomAd4. There are 351 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 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.3824A>G	p.Tyr1275Cys	missense	Exon 35 of 35	NP_004990.3
	MYO6	NM_001368865.1		c.3851A>G	p.Tyr1284Cys	missense	Exon 36 of 36	NP_001355794.1	A0A590UJ40
	MYO6	NM_001368866.1		c.3824A>G	p.Tyr1275Cys	missense	Exon 35 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.3824A>G	p.Tyr1275Cys	missense	Exon 35 of 35	ENSP00000358994.3	Q9UM54-1
	MYO6	ENST00000615563.4	TSL:1	c.3755A>G	p.Tyr1252Cys	missense	Exon 32 of 32	ENSP00000478013.1	Q9UM54-2
	MYO6	ENST00000664640.1		c.3851A>G	p.Tyr1284Cys	missense	Exon 36 of 36	ENSP00000499278.1	A0A590UJ40

Frequencies

GnomAD3 genomes AF: 0.00346 AC: 527 AN: 152168 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0101

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00366

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0272

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000735

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00636 AC: 1593 AN: 250560 AF XY: 0.00522

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.0267

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00332

Gnomad FIN exome AF: 0.0231

Gnomad NFE exome AF: 0.000706

Gnomad OTH exome AF: 0.00508

GnomAD4 exome AF: 0.00195 AC: 2844 AN: 1461342 Hom.: 40 Cov.: 31 AF XY: 0.00174 AC XY: 1268 AN XY: 726948

African (AFR) AF: 0.0000299 AC: 1 AN: 33468

American (AMR) AF: 0.0241 AC: 1078 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00275 AC: 109 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86198

European-Finnish (FIN) AF: 0.0236 AC: 1257 AN: 53338

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5542

European-Non Finnish (NFE) AF: 0.000245 AC: 272 AN: 1111950

Other (OTH) AF: 0.00209 AC: 126 AN: 60342

GnomAD4 genome AF: 0.00347 AC: 529 AN: 152286 Hom.: 6 Cov.: 32 AF XY: 0.00471 AC XY: 351 AN XY: 74464

African (AFR) AF: 0.000217 AC: 9 AN: 41570

American (AMR) AF: 0.0102 AC: 156 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00367 AC: 19 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.0272 AC: 289 AN: 10610

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

European-Non Finnish (NFE) AF: 0.000735 AC: 50 AN: 68024

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.000923 Hom.: 0

Bravo AF: 0.00235

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00520 AC: 631

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	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
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Benign	-0.049	T
BayesDel_noAF	Pathogenic	0.18
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.17	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D
MetaRNN	Benign	0.0094	T
MetaSVM	Uncertain	0.72	D
PhyloP100		7.1
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-2.1	N
REVEL	Pathogenic	0.65
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.016	D
Polyphen		1.0	D
Vest4		0.64
MVP		0.97
MPC		1.0
ClinPred		0.020	T
GERP RS		6.1
gMVP		0.77
Mutation Taster		=89/11	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

Other links and lift over

dbSNP: rs146461956; hg19: chr6-76624695; COSMIC: COSV106111483;