2-190056863-T-G

Variant names:

• chr2-190056863-T-G
• rs16823986
• NM_005259.3:c.*395A>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.*395A>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 0.0275 in 214,186 control chromosomes in the GnomAD database, including 382 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.038 (374 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (8 hom.)
• Consequence: MSTN NM_005259.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.400
• Publications: 1 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=-0.45).
• BP6: Variant 2-190056863-T-G is Benign according to our data. Variant chr2-190056863-T-G is described in ClinVar as [Benign]. Clinvar id is 333227.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.127 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSTN	NM_005259.3	c.*395A>C		3_prime_UTR_variant	Exon 3 of 3	ENST00000260950.5	NP_005250.1
AKAP19	XM_047446008.1	c.-517-23091T>G		intron_variant	Intron 2 of 6		XP_047301964.1
AKAP19	XM_047446009.1	c.-517-23091T>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.*395A>C		3_prime_UTR_variant	Exon 3 of 3	1	NM_005259.3	ENSP00000260950.3
C2orf88	ENST00000478197.1	n.220-22360T>G		intron_variant	Intron 1 of 1	4
C2orf88	ENST00000495546.1	n.202-23091T>G		intron_variant	Intron 1 of 2	4

Frequencies

GnomAD3 genomes AF: 0.0375 AC: 5705 AN: 152072 Hom.: 373 Cov.: 32

Gnomad AFR AF: 0.130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0154

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.0259

GnomAD4 exome AF: 0.00273 AC: 169 AN: 61996 Hom.: 8 Cov.: 0 AF XY: 0.00236 AC XY: 75 AN XY: 31748

African (AFR) AF: 0.102 AC: 113 AN: 1104

American (AMR) AF: 0.00726 AC: 27 AN: 3720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1442

East Asian (EAS) AF: 0.00 AC: 0 AN: 3380

South Asian (SAS) AF: 0.000376 AC: 3 AN: 7978

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.000107 AC: 4 AN: 37430

Other (OTH) AF: 0.00658 AC: 22 AN: 3344

GnomAD4 genome AF: 0.0376 AC: 5721 AN: 152190 Hom.: 374 Cov.: 32 AF XY: 0.0364 AC XY: 2713 AN XY: 74436

African (AFR) AF: 0.130 AC: 5409 AN: 41486

American (AMR) AF: 0.0154 AC: 235 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 68004

Other (OTH) AF: 0.0256 AC: 54 AN: 2110

Alfa AF: 0.0108 Hom.: 80

Bravo AF: 0.0428

Asia WGS AF: 0.00808 AC: 29 AN: 3478

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	-0.45
CADD	Benign	10
DANN	Benign	0.82
PhyloP100		0.40
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: rs16823986; hg19: chr2-190921589;