rs115598221

Variant names:

• chr5-137880801-T-C
• rs115598221
• NM_006790.3:c.634-15T>C

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.634-15T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000142 in 1,605,070 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00075 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000078 (0 hom.)
• Consequence: MYOT NM_006790.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.479
• Publications: 0 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 (BayesDel_noAF=-0.79).
• BP6: Variant 5-137880801-T-C is Benign according to our data. Variant chr5-137880801-T-C is described in ClinVar as Benign. ClinVar VariationId is 260038.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000755 (115/152342) while in subpopulation AFR AF = 0.00269 (112/41586). AF 95% confidence interval is 0.00229. There are 1 homozygotes in GnomAd4. There are 58 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 115 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.634-15T>C		intron	N/A	NP_006781.1
	MYOT	NM_001300911.2		c.289-15T>C		intron	N/A	NP_001287840.1
	MYOT	NM_001135940.2		c.82-15T>C		intron	N/A	NP_001129412.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYOT	ENST00000239926.9	TSL:1 MANE Select	c.634-15T>C		intron	N/A	ENSP00000239926.4
	MYOT	ENST00000968642.1		c.634-15T>C		intron	N/A	ENSP00000638701.1
	MYOT	ENST00000968644.1		c.634-15T>C		intron	N/A	ENSP00000638703.1

Frequencies

GnomAD3 genomes AF: 0.000755 AC: 115 AN: 152224 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00270

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000195 AC: 49 AN: 251000 AF XY: 0.000155

Gnomad AFR exome AF: 0.00283

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000778 AC: 113 AN: 1452728 Hom.: 0 Cov.: 28 AF XY: 0.0000608 AC XY: 44 AN XY: 723406

African (AFR) AF: 0.00298 AC: 99 AN: 33270

American (AMR) AF: 0.0000224 AC: 1 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26054

East Asian (EAS) AF: 0.00 AC: 0 AN: 39572

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86028

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 9.06e-7 AC: 1 AN: 1103870

Other (OTH) AF: 0.000183 AC: 11 AN: 60104

GnomAD4 genome AF: 0.000755 AC: 115 AN: 152342 Hom.: 1 Cov.: 32 AF XY: 0.000779 AC XY: 58 AN XY: 74502

African (AFR) AF: 0.00269 AC: 112 AN: 41586

American (AMR) AF: 0.0000653 AC: 1 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000408 Hom.: 0

Bravo AF: 0.000805

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Myofibrillar myopathy 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	13
DANN	Benign	0.67
PhyloP100		0.48
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs115598221; hg19: chr5-137216490;