rs12252199

Variant names:

• chr10-47323088-G-A
• rs12252199
• NM_016204.4:c.346+74G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-47323088-G-A
• chr10-47323088-G-T

Variant summary

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

The NM_016204.4(GDF2):​c.346+74G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.132 in 1,057,058 control chromosomes in the GnomAD database, including 10,074 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1829 hom., cov: 32)
  • Exomes 𝑓: 0.13 (8245 hom.)
• Consequence: GDF2 NM_016204.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.64
• Publications: 7 publications found

Genes affected

GDF2 (HGNC:4217): (growth differentiation factor 2) 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 regulates cartilage and bone development, angiogenesis and differentiation of cholinergic central nervous system neurons. Mutations in this gene are associated with hereditary hemorrhagic telangiectasia. [provided by RefSeq, Jul 2016]

GDF2 Gene-Disease associations (from GenCC):

• pulmonary arterial hypertension

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• telangiectasia, hereditary hemorrhagic, type 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• telangiectasia, hereditary hemorrhagic, type 5

  Inheritance: AD, Unknown, AR Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, G2P
• hereditary hemorrhagic telangiectasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 10-47323088-G-A is Benign according to our data. Variant chr10-47323088-G-A is described in ClinVar as Benign. ClinVar VariationId is 674696.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.22 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GDF2	NM_016204.4	c.346+74G>A		intron_variant	Intron 1 of 1	ENST00000581492.3	NP_057288.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GDF2	ENST00000581492.3	c.346+74G>A		intron_variant	Intron 1 of 1	1	NM_016204.4	ENSP00000463051.1

Frequencies

GnomAD3 genomes AF: 0.145 AC: 22109 AN: 152088 Hom.: 1823 Cov.: 32

Gnomad AFR AF: 0.223

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.0945

Gnomad ASJ AF: 0.131

Gnomad EAS AF: 0.00846

Gnomad SAS AF: 0.182

Gnomad FIN AF: 0.0882

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.128

Gnomad OTH AF: 0.145

GnomAD4 exome AF: 0.129 AC: 117111 AN: 904850 Hom.: 8245 AF XY: 0.131 AC XY: 59445 AN XY: 453820

African (AFR) AF: 0.233 AC: 5177 AN: 22232

American (AMR) AF: 0.0760 AC: 2283 AN: 30056

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 2469 AN: 17550

East Asian (EAS) AF: 0.00476 AC: 172 AN: 36162

South Asian (SAS) AF: 0.186 AC: 10278 AN: 55126

European-Finnish (FIN) AF: 0.0911 AC: 4302 AN: 47198

Middle Eastern (MID) AF: 0.115 AC: 451 AN: 3920

European-Non Finnish (NFE) AF: 0.133 AC: 86494 AN: 651548

Other (OTH) AF: 0.134 AC: 5485 AN: 41058

GnomAD4 genome AF: 0.146 AC: 22157 AN: 152208 Hom.: 1829 Cov.: 32 AF XY: 0.144 AC XY: 10683 AN XY: 74416

African (AFR) AF: 0.224 AC: 9282 AN: 41498

American (AMR) AF: 0.0945 AC: 1445 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.131 AC: 456 AN: 3472

East Asian (EAS) AF: 0.00848 AC: 44 AN: 5188

South Asian (SAS) AF: 0.182 AC: 878 AN: 4816

European-Finnish (FIN) AF: 0.0882 AC: 937 AN: 10620

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.128 AC: 8735 AN: 68004

Other (OTH) AF: 0.148 AC: 312 AN: 2114

Alfa AF: 0.122 Hom.: 761

Bravo AF: 0.149

Asia WGS AF: 0.142 AC: 494 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 16, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.3
DANN	Benign	0.59
PhyloP100		1.6

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: rs12252199; hg19: chr10-48416274;