chr5-137883575-G-T

Variant names:

• chr5-137883575-G-T
• rs142828368
• NM_006790.3:c.1008G>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_006790.3(MYOT):​c.1008G>T​(p.Val336Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00369 in 1,614,032 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0036 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (21 hom.)
• Consequence: MYOT NM_006790.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 1.33
• Publications: 1 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).
• BP6: Variant 5-137883575-G-T is Benign according to our data. Variant chr5-137883575-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 198548.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.33 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00361 (550/152250) while in subpopulation AMR AF = 0.00392 (60/15288). AF 95% confidence interval is 0.00344. There are 0 homozygotes in GnomAd4. There are 321 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 550 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.1008G>T	p.Val336Val	synonymous	Exon 7 of 10	NP_006781.1	A0A0C4DFM5
	MYOT	NM_001300911.2		c.663G>T	p.Val221Val	synonymous	Exon 8 of 11	NP_001287840.1	B4DT68
	MYOT	NM_001135940.2		c.456G>T	p.Val152Val	synonymous	Exon 7 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.1008G>T	p.Val336Val	synonymous	Exon 7 of 10	ENSP00000239926.4	A0A0C4DFM5
	MYOT	ENST00000968642.1		c.1005G>T	p.Val335Val	synonymous	Exon 7 of 10	ENSP00000638701.1
	MYOT	ENST00000968644.1		c.870G>T	p.Val290Val	synonymous	Exon 5 of 8	ENSP00000638703.1

Frequencies

GnomAD3 genomes AF: 0.00362 AC: 550 AN: 152132 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00393

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0185

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00382

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00397 AC: 998 AN: 251434 AF XY: 0.00394

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.00214

Gnomad ASJ exome AF: 0.00179

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0182

Gnomad NFE exome AF: 0.00422

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00370 AC: 5407 AN: 1461782 Hom.: 21 Cov.: 31 AF XY: 0.00365 AC XY: 2655 AN XY: 727208

African (AFR) AF: 0.000239 AC: 8 AN: 33478

American (AMR) AF: 0.00219 AC: 98 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00126 AC: 33 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.0179 AC: 955 AN: 53412

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00371 AC: 4129 AN: 1111922

Other (OTH) AF: 0.00301 AC: 182 AN: 60392

GnomAD4 genome AF: 0.00361 AC: 550 AN: 152250 Hom.: 0 Cov.: 32 AF XY: 0.00431 AC XY: 321 AN XY: 74458

African (AFR) AF: 0.000505 AC: 21 AN: 41546

American (AMR) AF: 0.00392 AC: 60 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.0185 AC: 196 AN: 10600

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

European-Non Finnish (NFE) AF: 0.00382 AC: 260 AN: 68018

Other (OTH) AF: 0.00378 AC: 8 AN: 2116

Alfa AF: 0.00282 Hom.: 2

Bravo AF: 0.00203

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00393

EpiControl AF: 0.00296

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	5	not provided (5)
-	-	3	Myofibrillar myopathy 3 (3)
-	-	1	Limb-Girdle Muscular Dystrophy, Dominant (1)
-	-	1	Myofibrillar Myopathy, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
CADD	Benign	5.8
DANN	Benign	0.80
PhyloP100		1.3
Mutation Taster		=100/0	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: rs142828368; hg19: chr5-137219264;