rs2295936

Positions:

• chr6-75887011-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.2658+17C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.3 in 1,595,250 control chromosomes in the GnomAD database, including 77,985 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (5162 hom., cov: 32)
  • Exomes 𝑓: 0.31 (72823 hom.)
• Consequence: MYO6 NM_004999.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.0240

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=-0.84).
• BP6: Variant 6-75887011-C-T is Benign according to our data. Variant chr6-75887011-C-T is described in ClinVar as [Benign]. Clinvar id is 45147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-75887011-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	Protein	UniProt
MYO6	NM_004999.4	c.2658+17C>T		intron_variant		ENST00000369977.8	NP_004990.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO6	ENST00000369977.8	c.2658+17C>T		intron_variant		1	NM_004999.4	ENSP00000358994	A1

Frequencies

GnomAD3 genomes AF: 0.228 AC: 34595 AN: 151846 Hom.: 5165 Cov.: 32

Gnomad AFR AF: 0.0588

Gnomad AMI AF: 0.317

Gnomad AMR AF: 0.206

Gnomad ASJ AF: 0.313

Gnomad EAS AF: 0.0521

Gnomad SAS AF: 0.262

Gnomad FIN AF: 0.256

Gnomad MID AF: 0.399

Gnomad NFE AF: 0.336

Gnomad OTH AF: 0.230

GnomAD3 exomes AF: 0.249 AC: 62289 AN: 249712 Hom.: 9232 AF XY: 0.263 AC XY: 35473 AN XY: 135122

Gnomad AFR exome AF: 0.0507

Gnomad AMR exome AF: 0.142

Gnomad ASJ exome AF: 0.309

Gnomad EAS exome AF: 0.0502

Gnomad SAS exome AF: 0.272

Gnomad FIN exome AF: 0.245

Gnomad NFE exome AF: 0.331

Gnomad OTH exome AF: 0.279

GnomAD4 exome AF: 0.307 AC: 443267 AN: 1443286 Hom.: 72823 Cov.: 30 AF XY: 0.308 AC XY: 221586 AN XY: 718842

Gnomad4 AFR exome AF: 0.0515

Gnomad4 AMR exome AF: 0.151

Gnomad4 ASJ exome AF: 0.308

Gnomad4 EAS exome AF: 0.0490

Gnomad4 SAS exome AF: 0.274

Gnomad4 FIN exome AF: 0.248

Gnomad4 NFE exome AF: 0.337

Gnomad4 OTH exome AF: 0.282

GnomAD4 genome AF: 0.228 AC: 34575 AN: 151964 Hom.: 5162 Cov.: 32 AF XY: 0.224 AC XY: 16601 AN XY: 74252

Gnomad4 AFR AF: 0.0587

Gnomad4 AMR AF: 0.205

Gnomad4 ASJ AF: 0.313

Gnomad4 EAS AF: 0.0524

Gnomad4 SAS AF: 0.261

Gnomad4 FIN AF: 0.256

Gnomad4 NFE AF: 0.336

Gnomad4 OTH AF: 0.226

Alfa AF: 0.282 Hom.: 1495

Bravo AF: 0.213

Asia WGS AF: 0.141 AC: 495 AN: 3476

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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 19, 2009	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 27, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Autosomal recessive nonsyndromic hearing loss 37 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Autosomal dominant nonsyndromic hearing loss 22 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Autosomal recessive nonsyndromic hearing loss 37;C2931767:Autosomal dominant nonsyndromic hearing loss 22 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 26, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.6
DANN	Benign	0.40

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: rs2295936; hg19: chr6-76596728;