Genetic Variant NM_016204.4:c.40_48dupTCCCTGCTG (chr10-47322699-C-CCCCTGCTGT) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM4BP6_ModerateBS1

The NM_016204.4(GDF2):c.40_48dupTCCCTGCTG(p.Ser14_Leu16dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000196 in 1,584,190 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00091 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

GDF2
NM_016204.4 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: 0.911

Publications

0 publications found

Variant links:

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), G2P, ClinGen
hereditary hemorrhagic telangiectasia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

GDF2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_016204.4.

BP6

Variant 10-47322699-C-CCCCTGCTGT is Benign according to our data. Variant chr10-47322699-C-CCCCTGCTGT is described in ClinVar as Likely_benign. ClinVar VariationId is 1110451.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000906 (138/152312) while in subpopulation AFR AF = 0.00322 (134/41566). AF 95% confidence interval is 0.00278. There are 0 homozygotes in GnomAd4. There are 70 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016204.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDF2	NM_016204.4	MANE Select	c.40_48dupTCCCTGCTG	p.Ser14_Leu16dup	conservative_inframe_insertion	Exon 1 of 2	NP_057288.1	Q9UK05

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDF2	ENST00000581492.3	TSL:1 MANE Select	c.40_48dupTCCCTGCTG	p.Ser14_Leu16dup	conservative_inframe_insertion	Exon 1 of 2	ENSP00000463051.1	Q9UK05

Frequencies

GnomAD3 genomes

AF:

0.000907

AC:

138

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00323

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000165

AC:

AN:

236356

AF XY:

0.000132

show subpopulations

Gnomad AFR exome

AF:

0.00250

Gnomad AMR exome

AF:

0.000119

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000120

AC:

172

AN:

1431878

Hom.:

Cov.:

AF XY:

0.0000933

AC XY:

AN XY:

707578

show subpopulations

African (AFR)

AF:

0.00438

AC:

144

AN:

32868

American (AMR)

AF:

0.000139

AC:

AN:

43060

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24884

East Asian (EAS)

AF:

0.00

AC:

AN:

38776

South Asian (SAS)

AF:

0.00

AC:

AN:

82964

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51308

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5658

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1093400

Other (OTH)

AF:

0.000373

AC:

AN:

58960

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000906

AC:

138

AN:

152312

Hom.:

Cov.:

AF XY:

0.000940

AC XY:

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.00322

AC:

134

AN:

41566

American (AMR)

AF:

0.000196

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68036

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000521

Hom.:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

GDF2-related disorder (1)

Telangiectasia, hereditary hemorrhagic, type 5 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.91

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over