rs12210963

Variant names:

• chr6-75835967-T-C
• rs12210963
• NM_004999.4:c.553+11T>C

Your query was ambiguous. Multiple possible variants found:

• chr6-75835967-T-C
• chr6-75835967-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004999.4(MYO6):​c.553+11T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.137 in 1,583,646 control chromosomes in the GnomAD database, including 15,861 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1365 hom., cov: 32)
  • Exomes 𝑓: 0.14 (14496 hom.)
• Consequence: MYO6 NM_004999.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.663
• Publications: 9 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: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• nonsyndromic genetic hearing loss

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

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 6-75835967-T-C is Benign according to our data. Variant chr6-75835967-T-C is described in ClinVar as Benign. ClinVar VariationId is 45164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.147 is higher than 0.05.

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.553+11T>C		intron	N/A	NP_004990.3
	MYO6	NM_001368865.1		c.553+11T>C		intron	N/A	NP_001355794.1	A0A590UJ40
	MYO6	NM_001368866.1		c.553+11T>C		intron	N/A	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.553+11T>C		intron	N/A	ENSP00000358994.3	Q9UM54-1
	MYO6	ENST00000615563.4	TSL:1	c.553+11T>C		intron	N/A	ENSP00000478013.1	Q9UM54-2
	MYO6	ENST00000664640.1		c.553+11T>C		intron	N/A	ENSP00000499278.1	A0A590UJ40

Frequencies

GnomAD3 genomes AF: 0.130 AC: 19814 AN: 152130 Hom.: 1365 Cov.: 32

Gnomad AFR AF: 0.115

Gnomad AMI AF: 0.110

Gnomad AMR AF: 0.133

Gnomad ASJ AF: 0.108

Gnomad EAS AF: 0.0373

Gnomad SAS AF: 0.0903

Gnomad FIN AF: 0.131

Gnomad MID AF: 0.140

Gnomad NFE AF: 0.150

Gnomad OTH AF: 0.146

GnomAD2 exomes AF: 0.118 AC: 29722 AN: 251136 AF XY: 0.120

Gnomad AFR exome AF: 0.113

Gnomad AMR exome AF: 0.0798

Gnomad ASJ exome AF: 0.103

Gnomad EAS exome AF: 0.0247

Gnomad FIN exome AF: 0.134

Gnomad NFE exome AF: 0.150

Gnomad OTH exome AF: 0.134

GnomAD4 exome AF: 0.138 AC: 197679 AN: 1431398 Hom.: 14496 Cov.: 26 AF XY: 0.137 AC XY: 97660 AN XY: 713956

African (AFR) AF: 0.110 AC: 3607 AN: 32866

American (AMR) AF: 0.0833 AC: 3722 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.106 AC: 2739 AN: 25938

East Asian (EAS) AF: 0.0503 AC: 1989 AN: 39526

South Asian (SAS) AF: 0.0926 AC: 7937 AN: 85700

European-Finnish (FIN) AF: 0.139 AC: 7403 AN: 53390

Middle Eastern (MID) AF: 0.107 AC: 610 AN: 5704

European-Non Finnish (NFE) AF: 0.149 AC: 161742 AN: 1084214

Other (OTH) AF: 0.134 AC: 7930 AN: 59368

GnomAD4 genome AF: 0.130 AC: 19817 AN: 152248 Hom.: 1365 Cov.: 32 AF XY: 0.128 AC XY: 9535 AN XY: 74436

African (AFR) AF: 0.115 AC: 4789 AN: 41548

American (AMR) AF: 0.133 AC: 2027 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 376 AN: 3468

East Asian (EAS) AF: 0.0374 AC: 194 AN: 5186

South Asian (SAS) AF: 0.0897 AC: 433 AN: 4826

European-Finnish (FIN) AF: 0.131 AC: 1385 AN: 10594

Middle Eastern (MID) AF: 0.137 AC: 40 AN: 292

European-Non Finnish (NFE) AF: 0.150 AC: 10169 AN: 68010

Other (OTH) AF: 0.144 AC: 304 AN: 2116

Alfa AF: 0.135 Hom.: 424

Bravo AF: 0.128

Asia WGS AF: 0.0680 AC: 236 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	3.3
DANN	Benign	0.52
PhyloP100		-0.66
Mutation Taster		=100/0	polymorphism (auto)

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: rs12210963; hg19: chr6-76545684; COSMIC: COSV64119165;