2-190060319-C-G

Variant names:

• chr2-190060319-C-G
• rs35781413
• NM_005259.3:c.490G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005259.3(MSTN):​c.490G>C​(p.Glu164Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E164K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSTN NM_005259.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.22
• Publications: 0 publications found

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]

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.083363235).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005259.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSTN	NM_005259.3	MANE Select	c.490G>C	p.Glu164Gln	missense	Exon 2 of 3	NP_005250.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSTN	ENST00000260950.5	TSL:1 MANE Select	c.490G>C	p.Glu164Gln	missense	Exon 2 of 3	ENSP00000260950.3
	C2orf88	ENST00000478197.1	TSL:4	n.220-18904C>G		intron	N/A
	C2orf88	ENST00000495546.1	TSL:4	n.202-19635C>G		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	9.4
DANN	Benign	0.79
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.0085	T
MetaRNN	Benign	0.083	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.69	N
PhyloP100		1.2
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.57	N
REVEL	Benign	0.031
Sift	Benign	0.43	T
Sift4G	Benign	0.59	T
Polyphen		0.0	B
Vest4		0.041
MutPred		0.45		Gain of MoRF binding (P = 0.0741)
MVP		0.43
MPC		0.24
ClinPred		0.14	T
GERP RS		1.6
Varity_R		0.22
gMVP		0.23
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs35781413; hg19: chr2-190925045;