rs121912561

Variant names:

• chr6-75886881-C-G
• NM_004999.4:c.2545C>G

Your query was ambiguous. Multiple possible variants found:

• chr6-75886881-C-G
• chr6-75886881-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004999.4(MYO6):​c.2545C>G​(p.Arg849Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 1.51

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO6	NM_004999.4	c.2545C>G	p.Arg849Gly	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.2545C>G	p.Arg849Gly	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 provided Uncertain:1

Jan 11, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T;.;.;.;T;T
Eigen	Benign	-0.058
Eigen_PC	Benign	0.014
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;.;D;D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.70	D;D;D;D;D;D
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	1.9	.;L;L;L;.;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.6	N;N;N;.;N;.
REVEL	Uncertain	0.48
Sift	Benign	0.19	T;T;T;.;T;.
Sift4G	Benign	0.43	T;T;T;T;T;T
Polyphen		0.58, 0.28	.;P;B;P;.;.
Vest4		0.72
MutPred		0.50		Loss of MoRF binding (P = 0.0218);Loss of MoRF binding (P = 0.0218);Loss of MoRF binding (P = 0.0218);Loss of MoRF binding (P = 0.0218);Loss of MoRF binding (P = 0.0218);Loss of MoRF binding (P = 0.0218);
MVP		0.95
MPC		0.33
ClinPred		0.91	D
GERP RS		4.0
gMVP		0.75

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-76596598;