chr2-190060351-T-C

Position:

chr2-190060351-T-C

Variant summary

Our verdict is Benign. Variant got -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. 13/20 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

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 made for transcript

Verdict is Benign. Variant got -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 id is 65688.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-190060351-T-C is described in Lovd as [Benign]. Variant chr2-190060351-T-C is described in Lovd as [Likely_pathogenic].

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/exons	MANE
MSTN	NM_005259.3 linkuse as main transcript	c.458A>G	p.Lys153Arg	missense_variant	2/3	ENST00000260950.5
C2orf88	XM_047446008.1 linkuse as main transcript	c.-517-19603T>C		intron_variant
C2orf88	XM_047446009.1 linkuse as main transcript	c.-517-19603T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
MSTN	ENST00000260950.5 linkuse as main transcript	c.458A>G	p.Lys153Arg	missense_variant	2/3	1	NM_005259.3	P1
C2orf88	ENST00000478197.1 linkuse as main transcript	n.220-18872T>C		intron_variant, non_coding_transcript_variant		4
C2orf88	ENST00000495546.1 linkuse as main transcript	n.202-19603T>C		intron_variant, non_coding_transcript_variant		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

GnomAD3 exomes

AF:

0.0278

AC:

6968

AN:

250548

Hom.:

390

AF XY:

0.0244

AC XY:

3309

AN XY:

135402

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 SAS exome

AF:

0.00828

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

Gnomad4 AFR exome

AF:

0.213

Gnomad4 AMR exome

AF:

0.0271

Gnomad4 ASJ exome

AF:

0.0593

Gnomad4 EAS exome

AF:

0.00111

Gnomad4 SAS exome

AF:

0.00855

Gnomad4 FIN exome

AF:

0.00159

Gnomad4 NFE exome

AF:

0.0146

Gnomad4 OTH exome

AF:

0.0314

GnomAD4 genome

AF:

0.0682

AC:

10374

AN:

152066

Hom.:

858

Cov.:

AF XY:

0.0655

AC XY:

4868

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.197

Gnomad4 AMR

AF:

0.0443

Gnomad4 ASJ

AF:

0.0634

Gnomad4 EAS

AF:

0.00155

Gnomad4 SAS

AF:

0.00726

Gnomad4 FIN

AF:

0.000847

Gnomad4 NFE

AF:

0.0161

Gnomad4 OTH

AF:

0.0615

Alfa

AF:

0.0291

Hom.:

347

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

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	This variant is associated with the following publications: (PMID: 25543063, 23354683, 19232494, 21283721) -

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

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

MutationTaster

Benign

0.043

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over