chr2-190060351-T-C

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.458A>G(p.Lys153Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0245 in 1,612,488 control chromosomes in the GnomAD database, including 1,911 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 (★★).

Frequency

Genomes: 𝑓 0.068 ( 858 hom., cov: 32)

Exomes 𝑓: 0.020 ( 1053 hom. )

Consequence

MSTN
NM_005259.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4O:1

Conservation

PhyloP100: 3.34

Publications

70 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=0.002616793).

BP6

Variant 2-190060351-T-C is Benign according to our data. Variant chr2-190060351-T-C is described in ClinVar as Benign. ClinVar VariationId is 65688.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.194 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSTN	NM_005259.3 link	c.458A>G	p.Lys153Arg	missense_variant	Exon 2 of 3	ENST00000260950.5	NP_005250.1	O14793Q53S46
AKAP19	XM_047446008.1 link	c.-517-19603T>C		intron_variant	Intron 2 of 6		XP_047301964.1
AKAP19	XM_047446009.1 link	c.-517-19603T>C		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.458A>G	p.Lys153Arg	missense_variant	Exon 2 of 3	1	NM_005259.3	ENSP00000260950.3	O14793
C2orf88	ENST00000478197.1 link	n.220-18872T>C		intron_variant	Intron 1 of 1	4
C2orf88	ENST00000495546.1 link	n.202-19603T>C		intron_variant	Intron 1 of 2	4

Frequencies

GnomAD3 genomes

AF:

0.0681

AC:

10350

AN:

151948

Hom.:

855

Cov.:

show subpopulations

Gnomad AFR

AF:

0.197

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.0444

Gnomad ASJ

AF:

0.0634

Gnomad EAS

AF:

0.00154

Gnomad SAS

AF:

0.00725

Gnomad FIN

AF:

0.000847

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0161

Gnomad OTH

AF:

0.0621

GnomAD2 exomes

AF:

0.0278

AC:

6968

AN:

250548

AF XY:

0.0244

show subpopulations

Gnomad AFR exome

AF:

0.202

Gnomad AMR exome

AF:

0.0249

Gnomad ASJ exome

AF:

0.0573

Gnomad EAS exome

AF:

0.00212

Gnomad FIN exome

AF:

0.00134

Gnomad NFE exome

AF:

0.0156

Gnomad OTH exome

AF:

0.0281

GnomAD4 exome

AF:

0.0200

AC:

29150

AN:

1460422

Hom.:

1053

Cov.:

AF XY:

0.0192

AC XY:

13976

AN XY:

726530

show subpopulations

African (AFR)

AF:

0.213

AC:

7105

AN:

33410

American (AMR)

AF:

0.0271

AC:

1211

AN:

44612

Ashkenazi Jewish (ASJ)

AF:

0.0593

AC:

1546

AN:

26068

East Asian (EAS)

AF:

0.00111

AC:

AN:

39670

South Asian (SAS)

AF:

0.00855

AC:

737

AN:

86182

European-Finnish (FIN)

AF:

0.00159

AC:

AN:

53376

Middle Eastern (MID)

AF:

0.0468

AC:

269

AN:

5748

European-Non Finnish (NFE)

AF:

0.0146

AC:

16261

AN:

1111040

Other (OTH)

AF:

0.0314

AC:

1892

AN:

60316

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

1432

2865

4297

5730

7162

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

708

1416

2124

2832

3540

<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:

0.0682

AC:

10374

AN:

152066

Hom.:

858

Cov.:

AF XY:

0.0655

AC XY:

4868

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.197

AC:

8183

AN:

41464

American (AMR)

AF:

0.0443

AC:

675

AN:

15244

Ashkenazi Jewish (ASJ)

AF:

0.0634

AC:

220

AN:

3468

East Asian (EAS)

AF:

0.00155

AC:

AN:

5174

South Asian (SAS)

AF:

0.00726

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.000847

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.0374

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0161

AC:

1093

AN:

67948

Other (OTH)

AF:

0.0615

AC:

130

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

447

894

1341

1788

2235

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

208

312

416

520

<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:

0.0329

Hom.:

942

Bravo

AF:

0.0776

TwinsUK

AF:

0.0148

AC:

ALSPAC

AF:

0.0169

AC:

ESP6500AA

AF:

0.206

AC:

906

ESP6500EA

AF:

0.0164

AC:

141

ExAC

AF:

0.0308

AC:

3744

Asia WGS

AF:

0.0150

AC:

AN:

3478

EpiCase

AF:

0.0187

EpiControl

AF:

0.0206

ClinVar

Significance: Benign

Submissions summary: Benign:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Myostatin-related muscle hypertrophy

Benign:2Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2017

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. -

not provided

Benign:2

Jun 09, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 25543063, 23354683, 19232494, 21283721) -

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

0.083

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.22

Eigen

Benign

-0.19

Eigen_PC

Benign

0.041

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.72

MetaRNN

Benign

0.0026

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.28

PhyloP100

3.3

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-0.11

REVEL

Benign

0.067

Sift

Benign

0.67

Sift4G

Benign

1.0

Polyphen

0.0010

Vest4

0.057

MPC

0.20

ClinPred

0.029

GERP RS

5.8

Varity_R

0.30

gMVP

0.40

Mutation Taster

=83/17

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