Genetic Variant MYH2:c.1975-9G>A (chr17-10535374-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_017534.6(MYH2):c.1975-9G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0599 in 1,611,432 control chromosomes in the GnomAD database, including 3,300 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.065 ( 356 hom., cov: 32)

Exomes 𝑓: 0.059 ( 2944 hom. )

Consequence

MYH2
NM_017534.6 intron

Scores

Splicing: ADA: 0.00002611

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -2.93

Publications

6 publications found

Variant links:

Genes affected

MYH2 (HGNC:7572): (myosin heavy chain 2) Myosins are actin-based motor proteins that function in the generation of mechanical force in eukaryotic cells. Muscle myosins are heterohexamers composed of 2 myosin heavy chains and 2 pairs of nonidentical myosin light chains. This gene encodes a member of the class II or conventional myosin heavy chains, and functions in skeletal muscle contraction. This gene is found in a cluster of myosin heavy chain genes on chromosome 17. A mutation in this gene results in inclusion body myopathy-3. Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Sep 2009]

MYH2 links:

MYHAS (HGNC:50609): (myosin heavy chain gene cluster antisense RNA) Predicted to enable primary miRNA binding activity. Predicted to be involved in response to muscle activity and skeletal muscle fiber development. Predicted to act upstream of or within with a positive effect on gene expression. Predicted to be located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

MYHAS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.67).

BP6

Variant 17-10535374-C-T is Benign according to our data. Variant chr17-10535374-C-T is described in ClinVar as Benign. ClinVar VariationId is 260816.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.116 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017534.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MYH2	NM_017534.6	MANE Select	c.1975-9G>A	intron	N/A	NP_060004.3
MYH2	NM_001100112.2		c.1975-9G>A	intron	N/A	NP_001093582.1	Q9UKX2-1
MYHAS	NR_125367.1		n.168-32163C>T	intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MYH2	ENST00000245503.10	TSL:1 MANE Select	c.1975-9G>A	intron	N/A	ENSP00000245503.5	Q9UKX2-1
MYH2	ENST00000532183.6	TSL:1	c.1974+1156G>A	intron	N/A	ENSP00000433944.1	Q9UKX2-2
MYH2	ENST00000622564.4	TSL:1	c.1974+1156G>A	intron	N/A	ENSP00000482463.1	Q9UKX2-2

Frequencies

GnomAD3 genomes

AF:

0.0645

AC:

9803

AN:

152018

Hom.:

348

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0800

Gnomad AMI

AF:

0.0581

Gnomad AMR

AF:

0.0488

Gnomad ASJ

AF:

0.0804

Gnomad EAS

AF:

0.0458

Gnomad SAS

AF:

0.124

Gnomad FIN

AF:

0.0525

Gnomad MID

AF:

0.0728

Gnomad NFE

AF:

0.0566

Gnomad OTH

AF:

0.0761

GnomAD2 exomes

AF:

0.0625

AC:

15663

AN:

250592

AF XY:

0.0652

show subpopulations

Gnomad AFR exome

AF:

0.0819

Gnomad AMR exome

AF:

0.0448

Gnomad ASJ exome

AF:

0.0828

Gnomad EAS exome

AF:

0.0404

Gnomad FIN exome

AF:

0.0544

Gnomad NFE exome

AF:

0.0549

Gnomad OTH exome

AF:

0.0602

GnomAD4 exome

AF:

0.0594

AC:

86662

AN:

1459296

Hom.:

2944

Cov.:

AF XY:

0.0609

AC XY:

44219

AN XY:

726134

show subpopulations

African (AFR)

AF:

0.0824

AC:

2753

AN:

33428

American (AMR)

AF:

0.0453

AC:

2024

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.0830

AC:

2168

AN:

26120

East Asian (EAS)

AF:

0.0377

AC:

1496

AN:

39678

South Asian (SAS)

AF:

0.112

AC:

9630

AN:

86188

European-Finnish (FIN)

AF:

0.0537

AC:

2866

AN:

53386

Middle Eastern (MID)

AF:

0.0586

AC:

338

AN:

5768

European-Non Finnish (NFE)

AF:

0.0554

AC:

61532

AN:

1109714

Other (OTH)

AF:

0.0639

AC:

3855

AN:

60308

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

4173

8347

12520

16694

20867

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2430

4860

7290

9720

12150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0647

AC:

9846

AN:

152136

Hom.:

356

Cov.:

AF XY:

0.0657

AC XY:

4888

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.0808

AC:

3352

AN:

41500

American (AMR)

AF:

0.0487

AC:

744

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.0804

AC:

279

AN:

3472

East Asian (EAS)

AF:

0.0455

AC:

235

AN:

5164

South Asian (SAS)

AF:

0.124

AC:

598

AN:

4814

European-Finnish (FIN)

AF:

0.0525

AC:

556

AN:

10586

Middle Eastern (MID)

AF:

0.0748

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0566

AC:

3846

AN:

68002

Other (OTH)

AF:

0.0762

AC:

161

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

478

956

1434

1912

2390

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

116

232

348

464

580

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0578

Hom.:

498

Bravo

AF:

0.0635

Asia WGS

AF:

0.0920

AC:

321

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

Myopathy, proximal, and ophthalmoplegia (2)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.67

CADD

Benign

1.3

(source)

DANN

Benign

0.74

PhyloP100

-2.9

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000026

dbscSNV1_RF

Benign

0.036

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over