Genetic Variant MSTN:c.373+5G>C (chr2-190062219-C-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_005259.3(MSTN):c.373+5G>C variant causes a splice region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,642 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MSTN
NM_005259.3 splice_region, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.53

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
MSTN	NM_005259.3 link	c.373+5G>C	splice_region_variant, intron_variant	Intron 1 of 2	ENST00000260950.5	NP_005250.1	O14793Q53S46
AKAP19	XM_047446008.1 link	c.-517-17735C>G	intron_variant	Intron 2 of 6		XP_047301964.1
AKAP19	XM_047446009.1 link	c.-517-17735C>G	intron_variant	Intron 1 of 5		XP_047301965.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
MSTN	ENST00000260950.5 link	c.373+5G>C	splice_region_variant, intron_variant	Intron 1 of 2	1	NM_005259.3	ENSP00000260950.3	O14793
C2orf88	ENST00000478197.1 link	n.220-17004C>G	intron_variant	Intron 1 of 1	4
C2orf88	ENST00000495546.1 link	n.202-17735C>G	intron_variant	Intron 1 of 2	4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460642

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726646

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33420

American (AMR)

AF:

0.00

AC:

AN:

44676

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26070

East Asian (EAS)

AF:

0.00

AC:

AN:

39678

South Asian (SAS)

AF:

0.00

AC:

AN:

86210

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111104

Other (OTH)

AF:

0.00

AC:

AN:

60328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.12

CADD

Uncertain

(source)

DANN

Uncertain

0.98

PhyloP100

7.5

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.96

SpliceAI score (max)

0.53

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.53

Position offset: 5

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over