rs12606

Variant names:

• chr6-75915024-C-T
• rs12606
• NM_004999.4:c.*12C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004999.4(MYO6):​c.*12C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.301 in 1,605,022 control chromosomes in the GnomAD database, including 78,954 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (5144 hom., cov: 32)
  • Exomes 𝑓: 0.31 (73810 hom.)
• Consequence: MYO6 NM_004999.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.0710
• Publications: 14 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 6-75915024-C-T is Benign according to our data. Variant chr6-75915024-C-T is described in ClinVar as Benign. ClinVar VariationId is 45130.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.332 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.*12C>T		3_prime_UTR	Exon 35 of 35	NP_004990.3
	MYO6	NM_001368865.1		c.*12C>T		3_prime_UTR	Exon 36 of 36	NP_001355794.1	A0A590UJ40
	MYO6	NM_001368866.1		c.*12C>T		3_prime_UTR	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.*12C>T		3_prime_UTR	Exon 35 of 35	ENSP00000358994.3	Q9UM54-1
	MYO6	ENST00000615563.4	TSL:1	c.*12C>T		3_prime_UTR	Exon 32 of 32	ENSP00000478013.1	Q9UM54-2
	MYO6	ENST00000664640.1		c.*12C>T		3_prime_UTR	Exon 36 of 36	ENSP00000499278.1	A0A590UJ40

Frequencies

GnomAD3 genomes AF: 0.227 AC: 34529 AN: 152028 Hom.: 5147 Cov.: 32

Gnomad AFR AF: 0.0584

Gnomad AMI AF: 0.316

Gnomad AMR AF: 0.206

Gnomad ASJ AF: 0.312

Gnomad EAS AF: 0.0522

Gnomad SAS AF: 0.257

Gnomad FIN AF: 0.254

Gnomad MID AF: 0.399

Gnomad NFE AF: 0.335

Gnomad OTH AF: 0.228

GnomAD2 exomes AF: 0.250 AC: 59988 AN: 239502 AF XY: 0.263

Gnomad AFR exome AF: 0.0513

Gnomad AMR exome AF: 0.143

Gnomad ASJ exome AF: 0.308

Gnomad EAS exome AF: 0.0505

Gnomad FIN exome AF: 0.247

Gnomad NFE exome AF: 0.333

Gnomad OTH exome AF: 0.282

GnomAD4 exome AF: 0.309 AC: 449403 AN: 1452876 Hom.: 73810 Cov.: 32 AF XY: 0.310 AC XY: 223868 AN XY: 722106

African (AFR) AF: 0.0516 AC: 1719 AN: 33324

American (AMR) AF: 0.152 AC: 6629 AN: 43752

Ashkenazi Jewish (ASJ) AF: 0.308 AC: 7997 AN: 25978

East Asian (EAS) AF: 0.0491 AC: 1938 AN: 39496

South Asian (SAS) AF: 0.271 AC: 23076 AN: 85258

European-Finnish (FIN) AF: 0.248 AC: 13140 AN: 52902

Middle Eastern (MID) AF: 0.384 AC: 1753 AN: 4564

European-Non Finnish (NFE) AF: 0.340 AC: 376152 AN: 1107604

Other (OTH) AF: 0.283 AC: 16999 AN: 59998

GnomAD4 genome AF: 0.227 AC: 34509 AN: 152146 Hom.: 5144 Cov.: 32 AF XY: 0.223 AC XY: 16556 AN XY: 74376

African (AFR) AF: 0.0583 AC: 2421 AN: 41534

American (AMR) AF: 0.205 AC: 3141 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.312 AC: 1083 AN: 3470

East Asian (EAS) AF: 0.0525 AC: 272 AN: 5182

South Asian (SAS) AF: 0.256 AC: 1234 AN: 4820

European-Finnish (FIN) AF: 0.254 AC: 2683 AN: 10556

Middle Eastern (MID) AF: 0.384 AC: 113 AN: 294

European-Non Finnish (NFE) AF: 0.335 AC: 22799 AN: 67980

Other (OTH) AF: 0.225 AC: 475 AN: 2112

Alfa AF: 0.303 Hom.: 5156

Bravo AF: 0.213

Asia WGS AF: 0.141 AC: 496 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Autosomal dominant nonsyndromic hearing loss 22 (2)
-	-	2	Autosomal recessive nonsyndromic hearing loss 37 (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.37
DANN	Benign	0.34
PhyloP100		-0.071
Mutation Taster		=100/0	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: rs12606; hg19: chr6-76624741; COSMIC: COSV64117463;