rs71578935

Positions:

• chr5-137875917-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006790.3(MYOT):​c.445G>C​(p.Glu149Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00184 in 1,614,074 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (9 hom.)
• Consequence: MYOT NM_006790.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 8.11

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006578535).
• BP6: Variant 5-137875917-G-C is Benign according to our data. Variant chr5-137875917-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 95440.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-137875917-G-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0015 (229/152298) while in subpopulation NFE AF= 0.0024 (163/68024). AF 95% confidence interval is 0.0021. There are 0 homozygotes in gnomad4. There are 95 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 229 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYOT	NM_006790.3	c.445G>C	p.Glu149Gln	missense_variant	3/10	ENST00000239926.9
PKD2L2-DT	XR_948815.3	n.302+12243C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYOT	ENST00000239926.9	c.445G>C	p.Glu149Gln	missense_variant	3/10	1	NM_006790.3	P1
PKD2L2-DT	ENST00000514616.6	n.319+12243C>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00150 AC: 229 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000983

Gnomad ASJ AF: 0.00865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00240

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00187 AC: 470 AN: 251404 Hom.: 5 AF XY: 0.00188 AC XY: 256 AN XY: 135866

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00214

Gnomad ASJ exome AF: 0.00734

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00254

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00187 AC: 2735 AN: 1461776 Hom.: 9 Cov.: 30 AF XY: 0.00192 AC XY: 1393 AN XY: 727194

Gnomad4 AFR exome AF: 0.000358

Gnomad4 AMR exome AF: 0.00199

Gnomad4 ASJ exome AF: 0.00739

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000348

Gnomad4 FIN exome AF: 0.000168

Gnomad4 NFE exome AF: 0.00202

Gnomad4 OTH exome AF: 0.00215

GnomAD4 genome AF: 0.00150 AC: 229 AN: 152298 Hom.: 0 Cov.: 32 AF XY: 0.00128 AC XY: 95 AN XY: 74474

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.000981

Gnomad4 ASJ AF: 0.00865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00240

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00234 Hom.: 2

Bravo AF: 0.00171

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00267 AC: 23

ExAC AF: 0.00184 AC: 223

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00305

EpiControl AF: 0.00373

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	MYOT: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 16, 2020	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 20, 2018	This variant is associated with the following publications: (PMID: 19240791) -

Myofibrillar myopathy 3 Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 23, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 08, 2020	- -

MYOT-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 21, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Heart failure Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Jul 03, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.0066	T;T
MetaSVM	Benign	-0.40	T
MutationTaster	Benign	0.92	D;D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-2.0	N;N
REVEL	Benign	0.28
Sift	Uncertain	0.0090	D;D
Sift4G	Uncertain	0.037	D;D
Vest4		0.25
MVP		0.92
MPC		0.66
ClinPred		0.045	T
GERP RS		5.7
gMVP		0.26

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

Publications

LitVar

Other links and lift over

dbSNP: rs71578935; hg19: chr5-137211606; COSMIC: COSV53516024; COSMIC: COSV53516024;