rs151094883

Variant names:

• chr5-137877605-G-A
• rs151094883
• NM_006790.3:c.617G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006790.3(MYOT):​c.617G>A​(p.Gly206Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000247 in 1,613,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G206G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00051 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: MYOT NM_006790.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.58
• Publications: 3 publications found

Genes affected

MYOT (HGNC:12399): (myotilin) This gene encodes a cystoskeletal protein which plays a significant role in the stability of thin filaments during muscle contraction. This protein binds F-actin, crosslinks actin filaments, and prevents latrunculin A-induced filament disassembly. Mutations in this gene have been associated with limb-girdle muscular dystrophy and myofibrillar myopathies. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined.[provided by RefSeq, Oct 2008]

PKD2L2-DT (HGNC:55557): (PKD2L2 divergent transcript)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0047349036).
• BP6: Variant 5-137877605-G-A is Benign according to our data. Variant chr5-137877605-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95441.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000512 (78/152262) while in subpopulation EAS AF = 0.0106 (55/5190). AF 95% confidence interval is 0.00836. There are 0 homozygotes in GnomAd4. There are 48 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 78 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006790.3. 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
	MYOT	NM_006790.3	MANE Select	c.617G>A	p.Gly206Asp	missense	Exon 4 of 10	NP_006781.1	A0A0C4DFM5
	MYOT	NM_001300911.2		c.272G>A	p.Gly91Asp	missense	Exon 5 of 11	NP_001287840.1	B4DT68
	MYOT	NM_001135940.2		c.65G>A	p.Gly22Asp	missense	Exon 4 of 10	NP_001129412.1	Q9UBF9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYOT	ENST00000239926.9	TSL:1 MANE Select	c.617G>A	p.Gly206Asp	missense	Exon 4 of 10	ENSP00000239926.4	A0A0C4DFM5
	MYOT	ENST00000968642.1		c.617G>A	p.Gly206Asp	missense	Exon 4 of 10	ENSP00000638701.1
	MYOT	ENST00000968644.1		c.617G>A	p.Gly206Asp	missense	Exon 3 of 8	ENSP00000638703.1

Frequencies

GnomAD3 genomes AF: 0.000506 AC: 77 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0104

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000676 AC: 170 AN: 251466 AF XY: 0.000684

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00701

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000176

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000220 AC: 321 AN: 1460760 Hom.: 0 Cov.: 30 AF XY: 0.000242 AC XY: 176 AN XY: 726778

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00348 AC: 138 AN: 39686

South Asian (SAS) AF: 0.000534 AC: 46 AN: 86220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000819 AC: 91 AN: 1111040

Other (OTH) AF: 0.000762 AC: 46 AN: 60354

GnomAD4 genome AF: 0.000512 AC: 78 AN: 152262 Hom.: 0 Cov.: 32 AF XY: 0.000645 AC XY: 48 AN XY: 74446

African (AFR) AF: 0.0000241 AC: 1 AN: 41562

American (AMR) AF: 0.0000654 AC: 1 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.0106 AC: 55 AN: 5190

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

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

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68012

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000192 Hom.: 0

Bravo AF: 0.000298

ExAC AF: 0.000733 AC: 89

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Myofibrillar myopathy 3 (3)
-	-	3	not provided (3)
-	-	1	Limb-Girdle Muscular Dystrophy, Dominant (1)
-	-	1	Myofibrillar Myopathy, Dominant (1)
-	-	1	MYOT-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	13
DANN	Benign	0.64
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.046	N
LIST_S2	Benign	0.34	T
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-0.99	T
PhyloP100		1.6
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.23	N
REVEL	Benign	0.14
Sift	Benign	0.89	T
Sift4G	Benign	0.57	T
Vest4		0.12
MVP		0.66
MPC		0.22
ClinPred		0.0024	T
GERP RS		4.5
gMVP		0.080
Mutation Taster		=91/9	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: rs151094883; hg19: chr5-137213294; COSMIC: COSV53514591; COSMIC: COSV53514591;