chr2-190062434-C-T

Variant names:

Variant summary

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

The NM_005259.3(MSTN):c.163G>A(p.Ala55Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00689 in 1,613,374 control chromosomes in the GnomAD database, including 660 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A55V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.037 ( 361 hom., cov: 32)

Exomes 𝑓: 0.0038 ( 299 hom. )

Consequence

MSTN
NM_005259.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3O:1

Conservation

PhyloP100: 1.96

Publications

24 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:

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 (MetaRNN=0.003504157).

BP6

Variant 2-190062434-C-T is Benign according to our data. Variant chr2-190062434-C-T is described in ClinVar as Benign. ClinVar VariationId is 65687.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.126 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSTN	NM_005259.3 link	c.163G>A	p.Ala55Thr	missense_variant	Exon 1 of 3	ENST00000260950.5	NP_005250.1	O14793Q53S46
AKAP19	XM_047446008.1 link	c.-517-17520C>T		intron_variant	Intron 2 of 6		XP_047301964.1
AKAP19	XM_047446009.1 link	c.-517-17520C>T		intron_variant	Intron 1 of 5		XP_047301965.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MSTN	ENST00000260950.5 link	c.163G>A	p.Ala55Thr	missense_variant	Exon 1 of 3	1	NM_005259.3	ENSP00000260950.3	O14793
C2orf88	ENST00000478197.1 link	n.220-16789C>T		intron_variant	Intron 1 of 1	4
C2orf88	ENST00000495546.1 link	n.202-17520C>T		intron_variant	Intron 1 of 2	4

Frequencies

GnomAD3 genomes

AF:

0.0370

AC:

5622

AN:

151932

Hom.:

360

Cov.:

show subpopulations

Gnomad AFR

AF:

0.129

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0151

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000309

Gnomad OTH

AF:

0.0259

GnomAD2 exomes

AF:

0.00982

AC:

2467

AN:

251222

AF XY:

0.00701

show subpopulations

Gnomad AFR exome

AF:

0.133

Gnomad AMR exome

AF:

0.00657

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000335

Gnomad OTH exome

AF:

0.00653

GnomAD4 exome

AF:

0.00375

AC:

5485

AN:

1461324

Hom.:

299

Cov.:

AF XY:

0.00324

AC XY:

2352

AN XY:

726964

show subpopulations

African (AFR)

AF:

0.131

AC:

4371

AN:

33450

American (AMR)

AF:

0.00777

AC:

347

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26106

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.000255

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00347

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000215

AC:

239

AN:

1111626

Other (OTH)

AF:

0.00805

AC:

486

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

303

607

910

1214

1517

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

148

296

444

592

740

<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:

0.0370

AC:

5633

AN:

152050

Hom.:

361

Cov.:

AF XY:

0.0361

AC XY:

2681

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.128

AC:

5326

AN:

41462

American (AMR)

AF:

0.0151

AC:

230

AN:

15236

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000414

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000309

AC:

AN:

67944

Other (OTH)

AF:

0.0256

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

239

478

717

956

1195

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

180

240

300

<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:

0.0135

Hom.:

305

Bravo

AF:

0.0424

ESP6500AA

AF:

0.129

AC:

567

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0119

AC:

1441

Asia WGS

AF:

0.00693

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Myostatin-related muscle hypertrophy

Benign:1Other:1

Feb 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

MSTN-related disorder

Benign:1

Jan 21, 2020

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.31

Eigen

Benign

-0.022

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.85

MetaRNN

Benign

0.0035

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

PhyloP100

2.0

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-0.67

REVEL

Benign

0.16

Sift

Benign

0.15

Sift4G

Benign

0.25

Polyphen

0.0

Vest4

0.052

MPC

0.24

ClinPred

0.019

GERP RS

5.5

PromoterAI

-0.022

Neutral

(source)

Varity_R

0.34

gMVP

0.65

Mutation Taster

=79/21

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over