rs6890689

Positions:

• chr5-137870871-C-A
• chr5-137870871-C-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_006790.3(MYOT):​c.220C>A​(p.Gln74Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00253 in 1,614,194 control chromosomes in the GnomAD database, including 88 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (44 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (44 hom.)
• Consequence: MYOT NM_006790.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.80

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07220766).
• BP6: Variant 5-137870871-C-A is Benign according to our data. Variant chr5-137870871-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 464369.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 = 0.0134 (2048/152308) while in subpopulation AFR AF= 0.0463 (1926/41554). AF 95% confidence interval is 0.0446. There are 44 homozygotes in gnomad4. There are 965 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2048 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYOT	NM_006790.3	c.220C>A	p.Gln74Lys	missense_variant	2/10	ENST00000239926.9	NP_006781.1
PKD2L2-DT	XR_948815.3	n.303-11608G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYOT	ENST00000239926.9	c.220C>A	p.Gln74Lys	missense_variant	2/10	1	NM_006790.3	ENSP00000239926	P1
PKD2L2-DT	ENST00000514616.6	n.320-11608G>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0134 AC: 2040 AN: 152190 Hom.: 44 Cov.: 32

Gnomad AFR AF: 0.0463

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00537

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.0119

GnomAD4 exome AF: 0.00140 AC: 2040 AN: 1461886 Hom.: 44 Cov.: 31 AF XY: 0.00121 AC XY: 877 AN XY: 727246

Gnomad4 AFR exome AF: 0.0470

Gnomad4 AMR exome AF: 0.00264

Gnomad4 ASJ exome AF: 0.000918

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000134

Gnomad4 OTH exome AF: 0.00253

GnomAD4 genome AF: 0.0134 AC: 2048 AN: 152308 Hom.: 44 Cov.: 32 AF XY: 0.0130 AC XY: 965 AN XY: 74488

Gnomad4 AFR AF: 0.0463

Gnomad4 AMR AF: 0.00536

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.00214 Hom.: 12

Bravo AF: 0.0159

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 09, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Sep 28, 2017

- -

Myofibrillar myopathy 3 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_noAF	Benign	-0.58
CADD	Benign	19
LIST_S2	Benign	0.54	T
MetaRNN	Benign	0.072	T
Sift4G	Benign	0.94	T
Vest4		0.91
gMVP		0.48

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs6890689; hg19: chr5-137206560;