rs375308029

Variant names:

• chr5-137877618-G-A
• rs375308029
• NM_006790.3:c.630G>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.630G>A​(p.Ser210Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000637 in 1,607,142 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00066 (25 hom.)
• Consequence: MYOT NM_006790.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.480
• 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=-0.56).
• BP6: Variant 5-137877618-G-A is Benign according to our data. Variant chr5-137877618-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 260037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000374 (57/152254) while in subpopulation SAS AF = 0.0112 (54/4816). AF 95% confidence interval is 0.00883. There are 0 homozygotes in GnomAd4. There are 36 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 57 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYOT	NM_006790.3	MANE Select	c.630G>A	p.Ser210Ser	synonymous	Exon 4 of 10	NP_006781.1
	MYOT	NM_001300911.2		c.285G>A	p.Ser95Ser	synonymous	Exon 5 of 11	NP_001287840.1
	MYOT	NM_001135940.2		c.78G>A	p.Ser26Ser	synonymous	Exon 4 of 10	NP_001129412.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYOT	ENST00000239926.9	TSL:1 MANE Select	c.630G>A	p.Ser210Ser	synonymous	Exon 4 of 10	ENSP00000239926.4
	MYOT	ENST00000515645.1	TSL:2	c.285G>A	p.Ser95Ser	synonymous	Exon 5 of 11	ENSP00000426281.1
	MYOT	ENST00000421631.6	TSL:2	c.78G>A	p.Ser26Ser	synonymous	Exon 4 of 10	ENSP00000391185.2

Frequencies

GnomAD3 genomes AF: 0.000375 AC: 57 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0112

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00152 AC: 381 AN: 251440 AF XY: 0.00208

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000664 AC: 966 AN: 1454888 Hom.: 25 Cov.: 28 AF XY: 0.000964 AC XY: 698 AN XY: 724328

African (AFR) AF: 0.0000300 AC: 1 AN: 33302

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26070

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39666

South Asian (SAS) AF: 0.0105 AC: 907 AN: 86116

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.00122 AC: 7 AN: 5744

European-Non Finnish (NFE) AF: 0.00000543 AC: 6 AN: 1105732

Other (OTH) AF: 0.000731 AC: 44 AN: 60166

GnomAD4 genome AF: 0.000374 AC: 57 AN: 152254 Hom.: 0 Cov.: 32 AF XY: 0.000484 AC XY: 36 AN XY: 74454

African (AFR) AF: 0.0000481 AC: 2 AN: 41538

American (AMR) AF: 0.00 AC: 0 AN: 15304

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.0112 AC: 54 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000226 Hom.: 0

Bravo AF: 0.0000793

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	5.2
DANN	Benign	0.72
PhyloP100		0.48
Mutation Taster		=98/2	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: rs375308029; hg19: chr5-137213307; COSMIC: COSV107268789; COSMIC: COSV107268789;