chr6-75844955-T-C

Variant names:

• chr6-75844955-T-C
• rs144038082
• NM_004999.4:c.875T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_004999.4(MYO6):​c.875T>C​(p.Leu292Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000522 in 1,613,330 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene MYO6 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.00059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00051 (2 hom.)
• Consequence: MYO6 NM_004999.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 2.09
• Publications: 5 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

Specifications for MYO6 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012707442).
• BP6: Variant 6-75844955-T-C is Benign according to our data. Variant chr6-75844955-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45167.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000591 (90/152294) while in subpopulation AMR AF = 0.00222 (34/15288). AF 95% confidence interval is 0.00164. There are 0 homozygotes in GnomAd4. There are 47 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

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.875T>C	p.Leu292Ser	missense	Exon 10 of 35	NP_004990.3
	MYO6	NM_001368865.1		c.875T>C	p.Leu292Ser	missense	Exon 10 of 36	NP_001355794.1	A0A590UJ40
	MYO6	NM_001368866.1		c.875T>C	p.Leu292Ser	missense	Exon 10 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.875T>C	p.Leu292Ser	missense	Exon 10 of 35	ENSP00000358994.3	Q9UM54-1
	MYO6	ENST00000615563.4	TSL:1	c.875T>C	p.Leu292Ser	missense	Exon 9 of 32	ENSP00000478013.1	Q9UM54-2
	MYO6	ENST00000664640.1		c.875T>C	p.Leu292Ser	missense	Exon 10 of 36	ENSP00000499278.1	A0A590UJ40

Frequencies

GnomAD3 genomes AF: 0.000591 AC: 90 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000750

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000490 AC: 123 AN: 251150 AF XY: 0.000390

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000573

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000515 AC: 752 AN: 1461036 Hom.: 2 Cov.: 31 AF XY: 0.000519 AC XY: 377 AN XY: 726910

African (AFR) AF: 0.0000598 AC: 2 AN: 33442

American (AMR) AF: 0.00183 AC: 82 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39588

South Asian (SAS) AF: 0.00 AC: 0 AN: 86220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.000578 AC: 642 AN: 1111424

Other (OTH) AF: 0.000431 AC: 26 AN: 60366

GnomAD4 genome AF: 0.000591 AC: 90 AN: 152294 Hom.: 0 Cov.: 32 AF XY: 0.000631 AC XY: 47 AN XY: 74466

African (AFR) AF: 0.0000962 AC: 4 AN: 41562

American (AMR) AF: 0.00222 AC: 34 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000750 AC: 51 AN: 68020

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000586 Hom.: 0

Bravo AF: 0.000782

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.000469 AC: 57

EpiCase AF: 0.000818

EpiControl AF: 0.000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	1	-	Autosomal recessive nonsyndromic hearing loss 37;C2931767:Autosomal dominant nonsyndromic hearing loss 22 (1)
-	-	1	MYO6-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	22
DANN	Benign	0.82
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.1
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	1.4	N
REVEL	Uncertain	0.32
Sift	Benign	0.74	T
Sift4G	Benign	0.73	T
Polyphen		0.17	B
Vest4		0.31
MVP		0.73
MPC		0.36
ClinPred		0.028	T
GERP RS		4.1
gMVP		0.43
Mutation Taster		=70/30	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: rs144038082; hg19: chr6-76554672;