6-75817566-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_004999.4(MYO6):​c.19G>C​(p.Val7Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)

Consequence

MYO6
NM_004999.4 missense

Scores

7
9
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.52

Publications

0 publications found
Variant links:
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: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia
  • nonsyndromic genetic hearing loss
    Inheritance: AD, AR Classification: DEFINITIVE, MODERATE Submitted by: ClinGen, G2P
  • autosomal recessive nonsyndromic hearing loss 37
    Inheritance: AR Classification: STRONG, MODERATE Submitted by: PanelApp Australia, 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

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.841

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MYO6NM_004999.4 linkc.19G>C p.Val7Leu missense_variant Exon 2 of 35 ENST00000369977.8 NP_004990.3 Q9UM54-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MYO6ENST00000369977.8 linkc.19G>C p.Val7Leu missense_variant Exon 2 of 35 1 NM_004999.4 ENSP00000358994.3 Q9UM54-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Jun 06, 2025
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.19G>C (p.V7L) alteration is located in exon 2 (coding exon 1) of the MYO6 gene. This alteration results from a G to C substitution at nucleotide position 19, causing the valine (V) at amino acid position 7 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.42
D
BayesDel_noAF
Pathogenic
0.36
CADD
Uncertain
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.38
T;.;.;.;T;T
Eigen
Pathogenic
0.85
Eigen_PC
Pathogenic
0.85
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.96
D;.;D;D;D;D
M_CAP
Uncertain
0.14
D
MetaRNN
Pathogenic
0.84
D;D;D;D;D;D
MetaSVM
Pathogenic
0.89
D
MutationAssessor
Uncertain
2.1
.;M;M;M;.;.
PhyloP100
9.5
PrimateAI
Uncertain
0.77
T
PROVEAN
Uncertain
-2.6
D;D;D;.;D;.
REVEL
Pathogenic
0.85
Sift
Uncertain
0.025
D;D;D;.;D;.
Sift4G
Uncertain
0.030
D;D;D;D;D;D
Polyphen
0.87, 0.94
.;P;P;P;.;.
Vest4
0.91
MutPred
0.54
Loss of methylation at K5 (P = 0.0613);Loss of methylation at K5 (P = 0.0613);Loss of methylation at K5 (P = 0.0613);Loss of methylation at K5 (P = 0.0613);Loss of methylation at K5 (P = 0.0613);Loss of methylation at K5 (P = 0.0613);
MVP
0.92
MPC
0.26
ClinPred
0.89
D
GERP RS
5.6
PromoterAI
-0.022
Neutral
gMVP
0.63
Mutation Taster
=27/73
disease causing

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

Other links and lift over

hg19: chr6-76527283; API