rs6890689

Variant names:

• chr5-137870871-C-A
• rs6890689
• NM_006790.3:c.220C>A

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 34 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 -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2048 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.220C>A	p.Gln74Lys	missense	Exon 2 of 10	NP_006781.1
	MYOT	NM_001300911.2		c.-120-6C>A		splice_region intron	N/A	NP_001287840.1
	MYOT	NM_001135940.2		c.-197+346C>A		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.220C>A	p.Gln74Lys	missense	Exon 2 of 10	ENSP00000239926.4
	MYOT	ENST00000515645.1	TSL:2	c.-120-6C>A		splice_region intron	N/A	ENSP00000426281.1
	MYOT	ENST00000421631.6	TSL:2	c.-197+346C>A		intron	N/A	ENSP00000391185.2

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

African (AFR) AF: 0.0470 AC: 1573 AN: 33480

American (AMR) AF: 0.00264 AC: 118 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000918 AC: 24 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5768

European-Non Finnish (NFE) AF: 0.000134 AC: 149 AN: 1112004

Other (OTH) AF: 0.00253 AC: 153 AN: 60396

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

African (AFR) AF: 0.0463 AC: 1926 AN: 41554

American (AMR) AF: 0.00536 AC: 82 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68034

Other (OTH) AF: 0.0118 AC: 25 AN: 2116

Alfa AF: 0.00476 Hom.: 29

Bravo AF: 0.0159

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		3.8
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

Other links and lift over

dbSNP: rs6890689; hg19: chr5-137206560;