2-190056055-C-G

Variant names:

• chr2-190056055-C-G
• rs3187415
• NM_005259.3:c.*1203G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BA1

The NM_005259.3(MSTN):​c.*1203G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.069 in 151,908 control chromosomes in the GnomAD database, including 856 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.069 (856 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MSTN NM_005259.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.32
• Publications: 2 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 2-190056055-C-G is Benign according to our data. Variant chr2-190056055-C-G is described in ClinVar as [Benign]. Clinvar id is 333219.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.195 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSTN	NM_005259.3	c.*1203G>C		3_prime_UTR_variant	Exon 3 of 3	ENST00000260950.5	NP_005250.1
AKAP19	XM_047446008.1	c.-517-23899C>G		intron_variant	Intron 2 of 6		XP_047301964.1
AKAP19	XM_047446009.1	c.-517-23899C>G		intron_variant	Intron 1 of 5		XP_047301965.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSTN	ENST00000260950.5	c.*1203G>C		3_prime_UTR_variant	Exon 3 of 3	1	NM_005259.3	ENSP00000260950.3
C2orf88	ENST00000478197.1	n.220-23168C>G		intron_variant	Intron 1 of 1	4
C2orf88	ENST00000495546.1	n.202-23899C>G		intron_variant	Intron 1 of 2	4

Frequencies

GnomAD3 genomes AF: 0.0689 AC: 10455 AN: 151790 Hom.: 853 Cov.: 32

Gnomad AFR AF: 0.198

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0456

Gnomad ASJ AF: 0.0620

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.00748

Gnomad FIN AF: 0.000851

Gnomad MID AF: 0.0355

Gnomad NFE AF: 0.0170

Gnomad OTH AF: 0.0633

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 432 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 260

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 426

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 2

Other (OTH) AF: 0.00 AC: 0 AN: 4

GnomAD4 genome AF: 0.0690 AC: 10478 AN: 151908 Hom.: 856 Cov.: 32 AF XY: 0.0663 AC XY: 4925 AN XY: 74270

African (AFR) AF: 0.198 AC: 8211 AN: 41414

American (AMR) AF: 0.0455 AC: 694 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.0620 AC: 215 AN: 3468

East Asian (EAS) AF: 0.00155 AC: 8 AN: 5174

South Asian (SAS) AF: 0.00749 AC: 36 AN: 4806

European-Finnish (FIN) AF: 0.000851 AC: 9 AN: 10580

Middle Eastern (MID) AF: 0.0347 AC: 10 AN: 288

European-Non Finnish (NFE) AF: 0.0170 AC: 1153 AN: 67898

Other (OTH) AF: 0.0626 AC: 132 AN: 2108

Alfa AF: 0.00592 Hom.: 6

Bravo AF: 0.0784

Asia WGS AF: 0.0140 AC: 48 AN: 3448

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Myostatin-related muscle hypertrophy Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.36
CADD	Benign	11
DANN	Benign	0.86
PhyloP100		1.3
Mutation Taster		=100/0	polymorphism (auto)

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: rs3187415; hg19: chr2-190920781;