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: Labcorp Genetics (formerly Invitae), Ambry Genetics
• nonsyndromic genetic hearing loss

  Inheritance: AD, AR Classification: DEFINITIVE, MODERATE Submitted by: G2P, ClinGen
• autosomal recessive nonsyndromic hearing loss 37

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: 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).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004999.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO6	NM_004999.4	MANE Select	c.2548C>G	p.Leu850Val	missense	Exon 25 of 35	NP_004990.3
	MYO6	NM_001368865.1		c.2548C>G	p.Leu850Val	missense	Exon 25 of 36	NP_001355794.1	A0A590UJ40
	MYO6	NM_001368866.1		c.2548C>G	p.Leu850Val	missense	Exon 25 of 35	NP_001355795.1	A0A1Y0BRN3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO6	ENST00000369977.8	TSL:1 MANE Select	c.2548C>G	p.Leu850Val	missense	Exon 25 of 35	ENSP00000358994.3	Q9UM54-1
	MYO6	ENST00000615563.4	TSL:1	c.2548C>G	p.Leu850Val	missense	Exon 24 of 32	ENSP00000478013.1	Q9UM54-2
	MYO6	ENST00000664640.1		c.2548C>G	p.Leu850Val	missense	Exon 25 of 36	ENSP00000499278.1	A0A590UJ40

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	0.042
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.32	T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	1.4	L
PhyloP100		4.8
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.32
Sift	Benign	0.17	T
Sift4G	Benign	0.67	T
Polyphen		0.36	B
Vest4		0.44
MutPred		0.44		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;