6-75817304-C-CAAAA

Variant names:

• chr6-75817304-C-CAAAA
• rs759910571
• NM_004999.4:c.-47-182_-47-179dupAAAA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_004999.4(MYO6):​c.-47-182_-47-179dupAAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0429 in 62,818 control chromosomes in the GnomAD database, including 86 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.043 (86 hom., cov: 31)
• Consequence: MYO6 NM_004999.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.194
• 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: Benign. The variant received -10 ACMG points.

• BP6: Variant 6-75817304-C-CAAAA is Benign according to our data. Variant chr6-75817304-C-CAAAA is described in ClinVar as [Benign]. Clinvar id is 1287413.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.178 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO6	NM_004999.4	c.-47-182_-47-179dupAAAA		intron_variant	Intron 1 of 34	ENST00000369977.8	NP_004990.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO6	ENST00000369977.8	c.-47-197_-47-196insAAAA		intron_variant	Intron 1 of 34	1	NM_004999.4	ENSP00000358994.3

Frequencies

GnomAD3 genomes AF: 0.0429 AC: 2692 AN: 62798 Hom.: 87 Cov.: 31

Gnomad AFR AF: 0.0833

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0322

Gnomad ASJ AF: 0.0139

Gnomad EAS AF: 0.191

Gnomad SAS AF: 0.0216

Gnomad FIN AF: 0.0766

Gnomad MID AF: 0.0395

Gnomad NFE AF: 0.00367

Gnomad OTH AF: 0.0284

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0429 AC: 2698 AN: 62818 Hom.: 86 Cov.: 31 AF XY: 0.0445 AC XY: 1318 AN XY: 29600

African (AFR) AF: 0.0835 AC: 1600 AN: 19158

American (AMR) AF: 0.0322 AC: 170 AN: 5280

Ashkenazi Jewish (ASJ) AF: 0.0139 AC: 21 AN: 1514

East Asian (EAS) AF: 0.191 AC: 520 AN: 2720

South Asian (SAS) AF: 0.0217 AC: 46 AN: 2124

European-Finnish (FIN) AF: 0.0766 AC: 211 AN: 2754

Middle Eastern (MID) AF: 0.0417 AC: 3 AN: 72

European-Non Finnish (NFE) AF: 0.00367 AC: 103 AN: 28060

Other (OTH) AF: 0.0280 AC: 24 AN: 856

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Sep 08, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.19
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs759910571; hg19: chr6-76527021;