2-190057123-C-T

Variant names:

• chr2-190057123-C-T
• rs60490864
• NM_005259.3:c.*135G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005259.3(MSTN):​c.*135G>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 0.00499 in 862,534 control chromosomes in the GnomAD database, including 131 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (94 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (37 hom.)
• Consequence: MSTN NM_005259.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.242
• Publications: 0 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 2-190057123-C-T is Benign according to our data. Variant chr2-190057123-C-T is described in ClinVar as [Benign]. Clinvar id is 333231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.063 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSTN	NM_005259.3	c.*135G>A		3_prime_UTR_variant	Exon 3 of 3	ENST00000260950.5	NP_005250.1
AKAP19	XM_047446008.1	c.-517-22831C>T		intron_variant	Intron 2 of 6		XP_047301964.1
AKAP19	XM_047446009.1	c.-517-22831C>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.*135G>A		3_prime_UTR_variant	Exon 3 of 3	1	NM_005259.3	ENSP00000260950.3
C2orf88	ENST00000478197.1	n.220-22100C>T		intron_variant	Intron 1 of 1	4
C2orf88	ENST00000495546.1	n.202-22831C>T		intron_variant	Intron 1 of 2	4

Frequencies

GnomAD3 genomes AF: 0.0187 AC: 2847 AN: 151964 Hom.: 94 Cov.: 32

Gnomad AFR AF: 0.0652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00657

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000280

Gnomad OTH AF: 0.0134

GnomAD4 exome AF: 0.00204 AC: 1452 AN: 710452 Hom.: 37 Cov.: 9 AF XY: 0.00173 AC XY: 637 AN XY: 367456

African (AFR) AF: 0.0650 AC: 1114 AN: 17132

American (AMR) AF: 0.00417 AC: 95 AN: 22766

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16810

East Asian (EAS) AF: 0.00 AC: 0 AN: 32782

South Asian (SAS) AF: 0.000112 AC: 6 AN: 53722

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42240

Middle Eastern (MID) AF: 0.000788 AC: 2 AN: 2538

European-Non Finnish (NFE) AF: 0.000131 AC: 64 AN: 487924

Other (OTH) AF: 0.00495 AC: 171 AN: 34538

GnomAD4 genome AF: 0.0187 AC: 2849 AN: 152082 Hom.: 94 Cov.: 32 AF XY: 0.0179 AC XY: 1330 AN XY: 74346

African (AFR) AF: 0.0651 AC: 2701 AN: 41496

American (AMR) AF: 0.00656 AC: 100 AN: 15248

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000280 AC: 19 AN: 67966

Other (OTH) AF: 0.0133 AC: 28 AN: 2104

Alfa AF: 0.0102 Hom.: 9

Bravo AF: 0.0212

Asia WGS AF: 0.00635 AC: 22 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Myostatin-related muscle hypertrophy Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	6.0
DANN	Benign	0.61
PhyloP100		0.24
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: rs60490864; hg19: chr2-190921849;