chr2-190056516-G-A

Position:

• chr2-190056516-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_005259.3(MSTN):​c.*742C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.058 in 152,552 control chromosomes in the GnomAD database, including 378 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.058 (378 hom., cov: 32)
  • Exomes 𝑓: 0.041 (0 hom.)
• Consequence: MSTN NM_005259.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.00800

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

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 2-190056516-G-A is Benign according to our data. Variant chr2-190056516-G-A is described in ClinVar as [Benign]. Clinvar id is 333223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0883 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSTN	NM_005259.3	c.*742C>T		3_prime_UTR_variant	3/3	ENST00000260950.5	NP_005250.1
C2orf88	XM_047446008.1	c.-517-23438G>A		intron_variant			XP_047301964.1
C2orf88	XM_047446009.1	c.-517-23438G>A		intron_variant			XP_047301965.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSTN	ENST00000260950.5	c.*742C>T		3_prime_UTR_variant	3/3	1	NM_005259.3	ENSP00000260950	P1
C2orf88	ENST00000478197.1	n.220-22707G>A		intron_variant, non_coding_transcript_variant		4
C2orf88	ENST00000495546.1	n.202-23438G>A		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.0581 AC: 8829 AN: 152046 Hom.: 378 Cov.: 32

Gnomad AFR AF: 0.0169

Gnomad AMI AF: 0.341

Gnomad AMR AF: 0.0483

Gnomad ASJ AF: 0.0309

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0684

Gnomad FIN AF: 0.0363

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0902

Gnomad OTH AF: 0.0493

GnomAD4 exome AF: 0.0412 AC: 16 AN: 388 Hom.: 0 Cov.: 0 AF XY: 0.0474 AC XY: 11 AN XY: 232

Gnomad4 FIN exome AF: 0.0419

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0580 AC: 8825 AN: 152164 Hom.: 378 Cov.: 32 AF XY: 0.0550 AC XY: 4091 AN XY: 74368

Gnomad4 AFR AF: 0.0168

Gnomad4 AMR AF: 0.0482

Gnomad4 ASJ AF: 0.0309

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.0682

Gnomad4 FIN AF: 0.0363

Gnomad4 NFE AF: 0.0902

Gnomad4 OTH AF: 0.0488

Alfa AF: 0.0751 Hom.: 83

Bravo AF: 0.0575

Asia WGS AF: 0.0220 AC: 77 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Myostatin-related muscle hypertrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	8.6
DANN	Benign	0.67

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: rs72909336; hg19: chr2-190921242;