2-190056985-G-C

Position:

• chr2-190056985-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005259.3(MSTN):​c.*273C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0143 in 362,862 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (16 hom., cov: 32)
  • Exomes 𝑓: 0.016 (47 hom.)
• Consequence: MSTN NM_005259.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.905

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 2-190056985-G-C is Benign according to our data. Variant chr2-190056985-G-C is described in ClinVar as [Benign]. Clinvar id is 333229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0125 (1894/152082) while in subpopulation NFE AF= 0.0196 (1331/67966). AF 95% confidence interval is 0.0187. There are 16 homozygotes in gnomad4. There are 854 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSTN	NM_005259.3	c.*273C>G		3_prime_UTR_variant	3/3	ENST00000260950.5
C2orf88	XM_047446008.1	c.-517-22969G>C		intron_variant
C2orf88	XM_047446009.1	c.-517-22969G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSTN	ENST00000260950.5	c.*273C>G		3_prime_UTR_variant	3/3	1	NM_005259.3	P1
C2orf88	ENST00000478197.1	n.220-22238G>C		intron_variant, non_coding_transcript_variant		4
C2orf88	ENST00000495546.1	n.202-22969G>C		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.0125 AC: 1896 AN: 151964 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.00365

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0175

Gnomad ASJ AF: 0.0173

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0196

Gnomad OTH AF: 0.0144

GnomAD4 exome AF: 0.0156 AC: 3290 AN: 210780 Hom.: 47 Cov.: 2 AF XY: 0.0154 AC XY: 1689 AN XY: 109640

Gnomad4 AFR exome AF: 0.00443

Gnomad4 AMR exome AF: 0.0156

Gnomad4 ASJ exome AF: 0.0151

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00649

Gnomad4 FIN exome AF: 0.00406

Gnomad4 NFE exome AF: 0.0202

Gnomad4 OTH exome AF: 0.0153

GnomAD4 genome AF: 0.0125 AC: 1894 AN: 152082 Hom.: 16 Cov.: 32 AF XY: 0.0115 AC XY: 854 AN XY: 74344

Gnomad4 AFR AF: 0.00364

Gnomad4 AMR AF: 0.0175

Gnomad4 ASJ AF: 0.0173

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.0196

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.00491 Hom.: 0

Bravo AF: 0.0136

Asia WGS AF: 0.00376 AC: 13 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	-0.86
CADD	Benign	2.8
DANN	Benign	0.65

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: rs150145410; hg19: chr2-190921711;