rs12606

chr6-75915024-C-T

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 45130.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-75915024-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.332 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO6	NM_004999.4	c.*12C>T		3_prime_UTR_variant	35/35	ENST00000369977.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO6	ENST00000369977.8	c.*12C>T		3_prime_UTR_variant	35/35	1	NM_004999.4	A1

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

GnomAD3 exomes AF: 0.250 AC: 59988 AN: 239502 Hom.: 8717 AF XY: 0.263 AC XY: 34032 AN XY: 129182

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 SAS exome AF: 0.270

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

Gnomad4 AFR exome AF: 0.0516

Gnomad4 AMR exome AF: 0.152

Gnomad4 ASJ exome AF: 0.308

Gnomad4 EAS exome AF: 0.0491

Gnomad4 SAS exome AF: 0.271

Gnomad4 FIN exome AF: 0.248

Gnomad4 NFE exome AF: 0.340

Gnomad4 OTH exome AF: 0.283

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

Gnomad4 AFR AF: 0.0583

Gnomad4 AMR AF: 0.205

Gnomad4 ASJ AF: 0.312

Gnomad4 EAS AF: 0.0525

Gnomad4 SAS AF: 0.256

Gnomad4 FIN AF: 0.254

Gnomad4 NFE AF: 0.335

Gnomad4 OTH AF: 0.225

Alfa AF: 0.303 Hom.: 4721

Bravo AF: 0.213

Asia WGS AF: 0.141 AC: 496 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 17, 2012	- -

Autosomal recessive nonsyndromic hearing loss 37 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

Autosomal dominant nonsyndromic hearing loss 22 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 03, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	0.37
Dann	Benign	0.34

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

Publications

LitVar

Other links and lift over

dbSNP: rs12606; hg19: chr6-76624741; COSMIC: COSV64117463;