rs71578935

Variant names:

• chr5-137875917-G-C
• rs71578935
• NM_006790.3:c.445G>C

Your query was ambiguous. Multiple possible variants found:

• chr5-137875917-G-C
• chr5-137875917-G-A
• chr5-137875917-G-T

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.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:12
• Conservation: PhyloP100: 8.11
• Publications: 8 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 (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 Benign/Likely_benign. ClinVar VariationId is 95440.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 229 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYOT	NM_006790.3	MANE Select	c.445G>C	p.Glu149Gln	missense	Exon 3 of 10	NP_006781.1	A0A0C4DFM5
	MYOT	NM_001300911.2		c.100G>C	p.Glu34Gln	missense	Exon 4 of 11	NP_001287840.1	B4DT68
	MYOT	NM_001135940.2		c.-108G>C		5_prime_UTR	Exon 3 of 10	NP_001129412.1	Q9UBF9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYOT	ENST00000239926.9	TSL:1 MANE Select	c.445G>C	p.Glu149Gln	missense	Exon 3 of 10	ENSP00000239926.4	A0A0C4DFM5
	MYOT	ENST00000968642.1		c.445G>C	p.Glu149Gln	missense	Exon 3 of 10	ENSP00000638701.1
	MYOT	ENST00000968644.1		c.445G>C	p.Glu149Gln	missense	Exon 2 of 8	ENSP00000638703.1

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

GnomAD2 exomes AF: 0.00187 AC: 470 AN: 251404 AF XY: 0.00188

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 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

African (AFR) AF: 0.000358 AC: 12 AN: 33476

American (AMR) AF: 0.00199 AC: 89 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00739 AC: 193 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.000348 AC: 30 AN: 86256

European-Finnish (FIN) AF: 0.000168 AC: 9 AN: 53418

Middle Eastern (MID) AF: 0.00503 AC: 29 AN: 5766

European-Non Finnish (NFE) AF: 0.00202 AC: 2243 AN: 1111952

Other (OTH) AF: 0.00215 AC: 130 AN: 60392

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

African (AFR) AF: 0.000361 AC: 15 AN: 41576

American (AMR) AF: 0.000981 AC: 15 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00865 AC: 30 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

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

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

European-Non Finnish (NFE) AF: 0.00240 AC: 163 AN: 68024

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	Myofibrillar myopathy 3 (3)
-	-	3	not specified (3)
-	-	1	Heart failure (1)
-	-	1	MYOT-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.0066	T
MetaSVM	Benign	-0.40	T
PhyloP100		8.1
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.28
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.037	D
Vest4		0.25
MVP		0.92
MPC		0.66
ClinPred		0.045	T
GERP RS		5.7
gMVP		0.26
Mutation Taster		=278/22	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: rs71578935; hg19: chr5-137211606; COSMIC: COSV53516024; COSMIC: COSV53516024;