rs2273857

chr6-75855236-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004999.4(MYO6):c.1176A>G(p.Thr392=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0163 in 1,613,670 control chromosomes in the GnomAD database, including 409 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (39 hom., cov: 32)
  • Exomes 𝑓: 0.017 (370 hom.)
• Consequence: MYO6 NM_004999.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.475

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 6-75855236-A-G is Benign according to our data. Variant chr6-75855236-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 45134.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-75855236-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.475 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0927 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO6	NM_004999.4	c.1176A>G	p.Thr392=	synonymous_variant	12/35	ENST00000369977.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO6	ENST00000369977.8	c.1176A>G	p.Thr392=	synonymous_variant	12/35	1	NM_004999.4	A1

Frequencies

GnomAD3 genomes AF: 0.0129 AC: 1957 AN: 152196 Hom.: 39 Cov.: 32

Gnomad AFR AF: 0.00330

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00864

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0998

Gnomad SAS AF: 0.00786

Gnomad FIN AF: 0.00979

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0146

Gnomad OTH AF: 0.0143

GnomAD3 exomes AF: 0.0164 AC: 4119 AN: 250890 Hom.: 119 AF XY: 0.0159 AC XY: 2162 AN XY: 135602

Gnomad AFR exome AF: 0.00265

Gnomad AMR exome AF: 0.00304

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.103

Gnomad SAS exome AF: 0.00422

Gnomad FIN exome AF: 0.0111

Gnomad NFE exome AF: 0.0142

Gnomad OTH exome AF: 0.0149

GnomAD4 exome AF: 0.0167 AC: 24415 AN: 1461356 Hom.: 370 Cov.: 31 AF XY: 0.0166 AC XY: 12087 AN XY: 726990

Gnomad4 AFR exome AF: 0.00218

Gnomad4 AMR exome AF: 0.00342

Gnomad4 ASJ exome AF: 0.000268

Gnomad4 EAS exome AF: 0.0921

Gnomad4 SAS exome AF: 0.00494

Gnomad4 FIN exome AF: 0.0121

Gnomad4 NFE exome AF: 0.0164

Gnomad4 OTH exome AF: 0.0196

GnomAD4 genome AF: 0.0128 AC: 1955 AN: 152314 Hom.: 39 Cov.: 32 AF XY: 0.0127 AC XY: 944 AN XY: 74480

Gnomad4 AFR AF: 0.00329

Gnomad4 AMR AF: 0.00863

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0998

Gnomad4 SAS AF: 0.00766

Gnomad4 FIN AF: 0.00979

Gnomad4 NFE AF: 0.0146

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.0126 Hom.: 13

Bravo AF: 0.0131

Asia WGS AF: 0.0400 AC: 140 AN: 3478

EpiCase AF: 0.0133

EpiControl AF: 0.0133

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 30, 2010	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 22, 2017	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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 15, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2024	- -

Autosomal recessive nonsyndromic hearing loss 37 Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Autosomal dominant nonsyndromic hearing loss 22 Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
Cadd	Benign	2.7
Dann	Benign	0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs2273857; hg19: chr6-76564953; COSMIC: COSV64118129;