5-137870773-T-C

Variant names:

• chr5-137870773-T-C
• rs587780396
• NM_006790.3:c.122T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006790.3(MYOT):​c.122T>C​(p.Ile41Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,196 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 32)
• Consequence: MYOT NM_006790.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: -0.277
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.021649778).

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.122T>C	p.Ile41Thr	missense	Exon 2 of 10	NP_006781.1
	MYOT	NM_001300911.2		c.-120-104T>C		intron	N/A	NP_001287840.1
	MYOT	NM_001135940.2		c.-197+248T>C		intron	N/A	NP_001129412.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYOT	ENST00000239926.9	TSL:1 MANE Select	c.122T>C	p.Ile41Thr	missense	Exon 2 of 10	ENSP00000239926.4
	MYOT	ENST00000968642.1		c.122T>C	p.Ile41Thr	missense	Exon 2 of 10	ENSP00000638701.1
	MYOT	ENST00000968644.1		c.122T>C	p.Ile41Thr	missense	Exon 1 of 8	ENSP00000638703.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152196 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74346

African (AFR) AF: 0.00 AC: 0 AN: 41448

American (AMR) AF: 0.000131 AC: 2 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.49
DANN	Benign	0.56
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.0080	T
MetaRNN	Benign	0.022	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.28
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.60	N
REVEL	Benign	0.14
Sift	Benign	0.42	T
Sift4G	Benign	0.48	T
Vest4		0.037
MutPred		0.25		Loss of stability (P = 0.0078)
MVP		0.24
MPC		0.21
ClinPred		0.21	T
GERP RS		-5.2
gMVP		0.27
Mutation Taster		=95/5	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: rs587780396; hg19: chr5-137206462;