Genetic Variant MSTN:c.747+625A>G (chr2-190059437-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_005259.3(MSTN):c.747+625A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.35 in 151,798 control chromosomes in the GnomAD database, including 13,305 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.35 ( 13305 hom., cov: 32)

Consequence

MSTN
NM_005259.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.77

Publications

6 publications found

Variant links:

Genes affected

MSTN (HGNC:4223): (myostatin) This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate each subunit of the disulfide-linked homodimer. This protein negatively regulates skeletal muscle cell proliferation and differentiation. Mutations in this gene are associated with increased skeletal muscle mass in humans and other mammals. [provided by RefSeq, Jul 2016]

MSTN links:

C2orf88 (HGNC:28191): (chromosome 2 open reading frame 88) Predicted to enable protein kinase A regulatory subunit binding activity. Predicted to be located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

C2orf88 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.708 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
MSTN	NM_005259.3 link	c.747+625A>G	intron_variant	Intron 2 of 2	ENST00000260950.5	NP_005250.1	O14793Q53S46
AKAP19	XM_047446008.1 link	c.-517-20517T>C	intron_variant	Intron 2 of 6		XP_047301964.1
AKAP19	XM_047446009.1 link	c.-517-20517T>C	intron_variant	Intron 1 of 5		XP_047301965.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
MSTN	ENST00000260950.5 link	c.747+625A>G	intron_variant	Intron 2 of 2	1	NM_005259.3	ENSP00000260950.3	O14793
C2orf88	ENST00000478197.1 link	n.220-19786T>C	intron_variant	Intron 1 of 1	4
C2orf88	ENST00000495546.1 link	n.202-20517T>C	intron_variant	Intron 1 of 2	4

Frequencies

GnomAD3 genomes

AF:

0.349

AC:

52998

AN:

151680

Hom.:

13252

Cov.:

show subpopulations

Gnomad AFR

AF:

0.714

Gnomad AMI

AF:

0.100

Gnomad AMR

AF:

0.266

Gnomad ASJ

AF:

0.304

Gnomad EAS

AF:

0.257

Gnomad SAS

AF:

0.170

Gnomad FIN

AF:

0.136

Gnomad MID

AF:

0.360

Gnomad NFE

AF:

0.205

Gnomad OTH

AF:

0.341

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.350

AC:

53112

AN:

151798

Hom.:

13305

Cov.:

AF XY:

0.341

AC XY:

25316

AN XY:

74212

show subpopulations

African (AFR)

AF:

0.714

AC:

29586

AN:

41410

American (AMR)

AF:

0.266

AC:

4045

AN:

15216

Ashkenazi Jewish (ASJ)

AF:

0.304

AC:

1053

AN:

3460

East Asian (EAS)

AF:

0.257

AC:

1328

AN:

5164

South Asian (SAS)

AF:

0.169

AC:

816

AN:

4822

European-Finnish (FIN)

AF:

0.136

AC:

1439

AN:

10588

Middle Eastern (MID)

AF:

0.353

AC:

103

AN:

292

European-Non Finnish (NFE)

AF:

0.205

AC:

13934

AN:

67836

Other (OTH)

AF:

0.341

AC:

717

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1352

2703

4055

5406

6758

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

458

916

1374

1832

2290

<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:

0.307

Hom.:

1339

Bravo

AF:

0.379

Asia WGS

AF:

0.249

AC:

866

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.67

(source)

DANN

Benign

0.72

PhyloP100

-1.8

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over