rs397517047

Variant names:

• chr6-75886884-C-G
• rs397517047
• NM_004999.4:c.2548C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004999.4(MYO6):​c.2548C>G​(p.Leu850Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.80
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31736368).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO6	NM_004999.4	c.2548C>G	p.Leu850Val	missense_variant	Exon 25 of 35	ENST00000369977.8	NP_004990.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO6	ENST00000369977.8	c.2548C>G	p.Leu850Val	missense_variant	Exon 25 of 35	1	NM_004999.4	ENSP00000358994.3

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

Submissions by phenotype

not specified Uncertain:1

Jul 28, 2010

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Benign. The Leu850Val varia nt in MYO6 has not been reported in the literature nor previously identified by our laboratory. This residue is conserved across mammals though not in lower spe cies; however, do not suggest a high likelihood of clinical significance. It sho uld be noted that this lab has only sequenced the MYO6 in 61 Caucasian individua ls such that the full spectrum of benign variation has not yet been defined for this gene, increasing the possibility that this may be a benign variant. In summ ary, the clinical significance of this variant cannot be determined with certain ty at this time; however based upon the arguments described above, we would lean towards a more likely benign role. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Uncertain	0.097	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T;.;.;.;T;T
Eigen	Benign	0.042
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;.;D;D;D;D
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.32	T;T;T;T;T;T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	1.4	.;L;L;L;.;.
PhyloP100		4.8
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.2	N;N;N;.;N;.
REVEL	Uncertain	0.32
Sift	Benign	0.17	T;T;T;.;T;.
Sift4G	Benign	0.67	T;T;T;T;T;T
Polyphen		0.36, 0.23	.;B;B;B;.;.
Vest4		0.44
MutPred		0.44		Loss of stability (P = 0.0451);Loss of stability (P = 0.0451);Loss of stability (P = 0.0451);Loss of stability (P = 0.0451);Loss of stability (P = 0.0451);Loss of stability (P = 0.0451);
MVP		0.83
MPC		0.26
ClinPred		0.61	D
GERP RS		5.9
gMVP		0.46
Mutation Taster		=84/16	polymorphism

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

Other links and lift over

dbSNP: rs397517047; hg19: chr6-76596601;