rs35781413

Positions:

chr2-190060319-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005259.3(MSTN):c.490G>A(p.Glu164Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00121 in 1,612,876 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0014 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 25 hom. )

Consequence

MSTN
NM_005259.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.22

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:

C2orf88 (HGNC:):

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=0.0031317472).

BP6

Variant 2-190060319-C-T is Benign according to our data. Variant chr2-190060319-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 333238.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-190060319-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00143 (217/151986) while in subpopulation EAS AF= 0.0283 (146/5166). AF 95% confidence interval is 0.0245. There are 1 homozygotes in gnomad4. There are 121 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 25 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSTN	NM_005259.3 linkuse as main transcript	c.490G>A	p.Glu164Lys	missense_variant	2/3	ENST00000260950.5	NP_005250.1	O14793Q53S46
C2orf88	XM_047446008.1 linkuse as main transcript	c.-517-19635C>T		intron_variant			XP_047301964.1
C2orf88	XM_047446009.1 linkuse as main transcript	c.-517-19635C>T		intron_variant			XP_047301965.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MSTN	ENST00000260950.5 linkuse as main transcript	c.490G>A	p.Glu164Lys	missense_variant	2/3	1	NM_005259.3	ENSP00000260950.3	O14793
C2orf88	ENST00000478197.1 linkuse as main transcript	n.220-18904C>T		intron_variant		4
C2orf88	ENST00000495546.1 linkuse as main transcript	n.202-19635C>T		intron_variant		4

Frequencies

GnomAD3 genomes

AF:

0.00143

AC:

217

AN:

151868

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000629

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00204

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0280

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.0000945

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000442

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00326

AC:

817

AN:

250792

Hom.:

AF XY:

0.00281

AC XY:

381

AN XY:

135498

show subpopulations

Gnomad AFR exome

AF:

0.000677

Gnomad AMR exome

AF:

0.00609

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0281

Gnomad SAS exome

AF:

0.00186

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00278

GnomAD4 exome

AF:

0.00119

AC:

1738

AN:

1460890

Hom.:

Cov.:

AF XY:

0.00113

AC XY:

823

AN XY:

726760

show subpopulations

Gnomad4 AFR exome

AF:

0.000419

Gnomad4 AMR exome

AF:

0.00540

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0264

Gnomad4 SAS exome

AF:

0.00208

Gnomad4 FIN exome

AF:

0.000150

Gnomad4 NFE exome

AF:

0.0000216

Gnomad4 OTH exome

AF:

0.00363

GnomAD4 genome

AF:

0.00143

AC:

217

AN:

151986

Hom.:

Cov.:

AF XY:

0.00163

AC XY:

121

AN XY:

74296

show subpopulations

Gnomad4 AFR

AF:

0.000627

Gnomad4 AMR

AF:

0.00197

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0283

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.0000945

Gnomad4 NFE

AF:

0.0000442

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00118

Hom.:

Bravo

AF:

0.00187

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00302

AC:

367

Asia WGS

AF:

0.0150

AC:

AN:

3478

EpiCase

AF:

0.0000546

EpiControl

AF:

0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 27, 2018	- -

Myostatin-related muscle hypertrophy

Benign:1

Likely 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.32

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.47

MetaRNN

Benign

0.0031

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.90

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.5

REVEL

Benign

0.075

Sift

Benign

0.47

Sift4G

Benign

0.41

Polyphen

0.0

Vest4

0.13

MVP

0.46

MPC

0.27

ClinPred

0.0052

GERP RS

1.6

Varity_R

0.11

gMVP

0.22

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