rs397517054

Positions:

• chr6-75840589-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_004999.4(MYO6):​c.558C>A​(p.Asn186Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,566 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MYO6 NM_004999.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.838

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.97

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO6	NM_004999.4	c.558C>A	p.Asn186Lys	missense_variant	8/35	ENST00000369977.8	NP_004990.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO6	ENST00000369977.8	c.558C>A	p.Asn186Lys	missense_variant	8/35	1	NM_004999.4	ENSP00000358994.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460566 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726712

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 29, 2012

The Asn186Lys variant (MYO6) has not been reported in the literature nor previou sly identified by our laboratory. Computational analyses (biochemical amino acid properties, conservation, PolyPhen2, and SIFT) suggest that the Asn186Lys varia nt may impact the protein, though this information is not predictive enough to d etermine pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.093	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	15
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;.;.;.;D;D
Eigen	Uncertain	0.34
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.30	N
LIST_S2	Uncertain	0.91	D;.;D;D;D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D
MetaSVM	Uncertain	0.76	D
MutationAssessor	Pathogenic	4.9	.;H;H;H;.;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.8	D;D;D;.;D;.
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0090	D;D;D;.;D;.
Sift4G	Uncertain	0.0020	D;D;D;D;D;D
Polyphen		0.95, 1.0	.;P;D;P;.;.
Vest4		0.96
MutPred		0.89		Gain of ubiquitination at N186 (P = 0.0428);Gain of ubiquitination at N186 (P = 0.0428);Gain of ubiquitination at N186 (P = 0.0428);Gain of ubiquitination at N186 (P = 0.0428);Gain of ubiquitination at N186 (P = 0.0428);Gain of ubiquitination at N186 (P = 0.0428);
MVP		0.94
MPC		0.30
ClinPred		0.96	D
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.89

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: rs397517054; hg19: chr6-76550306;