2-190056765-C-T

Variant names:

• chr2-190056765-C-T
• rs16832285
• NM_005259.3:c.*493G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005259.3(MSTN):​c.*493G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0646 in 164,046 control chromosomes in the GnomAD database, including 855 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.069 (847 hom., cov: 32)
  • Exomes 𝑓: 0.014 (8 hom.)
• Consequence: MSTN NM_005259.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.27
• Publications: 3 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 2-190056765-C-T is Benign according to our data. Variant chr2-190056765-C-T is described in ClinVar as [Benign]. Clinvar id is 333226.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.193 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSTN	NM_005259.3	c.*493G>A		3_prime_UTR_variant	Exon 3 of 3	ENST00000260950.5	NP_005250.1
AKAP19	XM_047446008.1	c.-517-23189C>T		intron_variant	Intron 2 of 6		XP_047301964.1
AKAP19	XM_047446009.1	c.-517-23189C>T		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.*493G>A		3_prime_UTR_variant	Exon 3 of 3	1	NM_005259.3	ENSP00000260950.3
C2orf88	ENST00000478197.1	n.220-22458C>T		intron_variant	Intron 1 of 1	4
C2orf88	ENST00000495546.1	n.202-23189C>T		intron_variant	Intron 1 of 2	4

Frequencies

GnomAD3 genomes AF: 0.0685 AC: 10410 AN: 151934 Hom.: 844 Cov.: 32

Gnomad AFR AF: 0.197

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0459

Gnomad ASJ AF: 0.0618

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.00725

Gnomad FIN AF: 0.000849

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0169

Gnomad OTH AF: 0.0631

GnomAD4 exome AF: 0.0143 AC: 172 AN: 11994 Hom.: 8 Cov.: 0 AF XY: 0.0159 AC XY: 100 AN XY: 6294

African (AFR) AF: 0.150 AC: 9 AN: 60

American (AMR) AF: 0.0262 AC: 53 AN: 2026

Ashkenazi Jewish (ASJ) AF: 0.0882 AC: 6 AN: 68

East Asian (EAS) AF: 0.00155 AC: 1 AN: 644

South Asian (SAS) AF: 0.00569 AC: 7 AN: 1230

European-Finnish (FIN) AF: 0.00134 AC: 1 AN: 744

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 16

European-Non Finnish (NFE) AF: 0.0130 AC: 87 AN: 6714

Other (OTH) AF: 0.0163 AC: 8 AN: 492

GnomAD4 genome AF: 0.0686 AC: 10433 AN: 152052 Hom.: 847 Cov.: 32 AF XY: 0.0660 AC XY: 4907 AN XY: 74336

African (AFR) AF: 0.197 AC: 8164 AN: 41454

American (AMR) AF: 0.0458 AC: 698 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.0618 AC: 214 AN: 3464

East Asian (EAS) AF: 0.00154 AC: 8 AN: 5178

South Asian (SAS) AF: 0.00725 AC: 35 AN: 4826

European-Finnish (FIN) AF: 0.000849 AC: 9 AN: 10598

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0170 AC: 1152 AN: 67960

Other (OTH) AF: 0.0624 AC: 132 AN: 2114

Alfa AF: 0.0364 Hom.: 819

Bravo AF: 0.0780

Asia WGS AF: 0.0140 AC: 48 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	-0.51
CADD	Benign	13
DANN	Benign	0.67
PhyloP100		2.3
Mutation Taster		=99/1	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: rs16832285; hg19: chr2-190921491;