rs2293284

Positions:

• chr2-190060519-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005259.3(MSTN):​c.374-84A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0407 in 1,230,538 control chromosomes in the GnomAD database, including 3,472 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.093 (1399 hom., cov: 32)
  • Exomes 𝑓: 0.033 (2073 hom.)
• Consequence: MSTN NM_005259.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.23

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]

C2orf88 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 2-190060519-T-A is Benign according to our data. Variant chr2-190060519-T-A is described in ClinVar as [Benign]. Clinvar id is 1258180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.237 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSTN	NM_005259.3	c.374-84A>T		intron_variant		ENST00000260950.5	NP_005250.1
C2orf88	XM_047446008.1	c.-517-19435T>A		intron_variant			XP_047301964.1
C2orf88	XM_047446009.1	c.-517-19435T>A		intron_variant			XP_047301965.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSTN	ENST00000260950.5	c.374-84A>T		intron_variant		1	NM_005259.3	ENSP00000260950.3
C2orf88	ENST00000478197.1	n.220-18704T>A		intron_variant		4
C2orf88	ENST00000495546.1	n.202-19435T>A		intron_variant		4

Frequencies

GnomAD3 genomes AF: 0.0927 AC: 14075 AN: 151892 Hom.: 1396 Cov.: 32

Gnomad AFR AF: 0.241

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0949

Gnomad ASJ AF: 0.0716

Gnomad EAS AF: 0.174

Gnomad SAS AF: 0.0155

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0180

Gnomad OTH AF: 0.0877

GnomAD4 exome AF: 0.0333 AC: 35956 AN: 1078528 Hom.: 2073 AF XY: 0.0320 AC XY: 17538 AN XY: 547290

Gnomad4 AFR exome AF: 0.262

Gnomad4 AMR exome AF: 0.113

Gnomad4 ASJ exome AF: 0.0720

Gnomad4 EAS exome AF: 0.200

Gnomad4 SAS exome AF: 0.0161

Gnomad4 FIN exome AF: 0.00419

Gnomad4 NFE exome AF: 0.0169

Gnomad4 OTH exome AF: 0.0483

GnomAD4 genome AF: 0.0928 AC: 14108 AN: 152010 Hom.: 1399 Cov.: 32 AF XY: 0.0902 AC XY: 6703 AN XY: 74336

Gnomad4 AFR AF: 0.241

Gnomad4 AMR AF: 0.0954

Gnomad4 ASJ AF: 0.0716

Gnomad4 EAS AF: 0.175

Gnomad4 SAS AF: 0.0151

Gnomad4 FIN AF: 0.00226

Gnomad4 NFE AF: 0.0180

Gnomad4 OTH AF: 0.0863

Alfa AF: 0.0638 Hom.: 135

Bravo AF: 0.112

Asia WGS AF: 0.0720 AC: 248 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 20, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.030
DANN	Benign	0.27

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

Other links and lift over

dbSNP: rs2293284; hg19: chr2-190925245; COSMIC: COSV53621803;