1-218434190-G-C

Variant names:

• chr1-218434190-G-C
• rs10482810
• NM_003238.6:c.619G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003238.6(TGFB2):​c.619G>C​(p.Val207Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00498 in 1,614,148 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V207A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0034 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0051 (34 hom.)
• Consequence: TGFB2 NM_003238.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:2 B:17 O:1
• Conservation: PhyloP100: 7.75
• Publications: 17 publications found

Genes affected

TGFB2 (HGNC:11768): (transforming growth factor beta 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 a latency-associated peptide (LAP) and a mature peptide, and is found in either a latent form composed of a mature peptide homodimer, a LAP homodimer, and a latent TGF-beta binding protein, or in an active form consisting solely of the mature peptide homodimer. The mature peptide may also form heterodimers with other TGF-beta family members. Disruption of the TGF-beta/SMAD pathway has been implicated in a variety of human cancers. A chromosomal translocation that includes this gene is associated with Peters' anomaly, a congenital defect of the anterior chamber of the eye. Mutations in this gene may be associated with Loeys-Dietz syndrome. This gene encodes multiple isoforms that may undergo similar proteolytic processing. [provided by RefSeq, Aug 2016]

TGFB2 Gene-Disease associations (from GenCC):

• Loeys-Dietz syndrome 4

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: Unknown, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.014598221).
• BP6: Variant 1-218434190-G-C is Benign according to our data. Variant chr1-218434190-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 155837.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 = 0.00339 (517/152314) while in subpopulation NFE AF = 0.00544 (370/68028). AF 95% confidence interval is 0.00498. There are 2 homozygotes in GnomAd4. There are 240 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 517 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003238.6. 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
	TGFB2	NM_003238.6	MANE Select	c.619G>C	p.Val207Leu	missense	Exon 3 of 7	NP_003229.1	P61812-1
	TGFB2	NM_001135599.4		c.703G>C	p.Val235Leu	missense	Exon 4 of 8	NP_001129071.1	P61812-2
	TGFB2	NR_138148.2		n.1985G>C		non_coding_transcript_exon	Exon 3 of 7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFB2	ENST00000366930.9	TSL:1 MANE Select	c.619G>C	p.Val207Leu	missense	Exon 3 of 7	ENSP00000355897.4	P61812-1
	TGFB2	ENST00000366929.4	TSL:1	c.703G>C	p.Val235Leu	missense	Exon 4 of 8	ENSP00000355896.4	P61812-2
	TGFB2	ENST00000479322.1	TSL:3	n.65G>C		non_coding_transcript_exon	Exon 1 of 5

Frequencies

GnomAD3 genomes AF: 0.00340 AC: 517 AN: 152196 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00330

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00544

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00330 AC: 828 AN: 251286 AF XY: 0.00342

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.00147

Gnomad ASJ exome AF: 0.00467

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00402

Gnomad NFE exome AF: 0.00502

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.00514 AC: 7515 AN: 1461834 Hom.: 34 Cov.: 32 AF XY: 0.00502 AC XY: 3654 AN XY: 727212

African (AFR) AF: 0.000806 AC: 27 AN: 33480

American (AMR) AF: 0.00148 AC: 66 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00505 AC: 132 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39696

South Asian (SAS) AF: 0.00153 AC: 132 AN: 86252

European-Finnish (FIN) AF: 0.00367 AC: 196 AN: 53416

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00601 AC: 6685 AN: 1111968

Other (OTH) AF: 0.00452 AC: 273 AN: 60396

GnomAD4 genome AF: 0.00339 AC: 517 AN: 152314 Hom.: 2 Cov.: 33 AF XY: 0.00322 AC XY: 240 AN XY: 74486

African (AFR) AF: 0.00115 AC: 48 AN: 41576

American (AMR) AF: 0.00203 AC: 31 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00548 AC: 19 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00330 AC: 35 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00544 AC: 370 AN: 68028

Other (OTH) AF: 0.00473 AC: 10 AN: 2116

Alfa AF: 0.00483 Hom.: 1

Bravo AF: 0.00313

TwinsUK AF: 0.00647 AC: 24

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00547 AC: 47

ExAC AF: 0.00334 AC: 405

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00507

EpiControl AF: 0.00433

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	4	Loeys-Dietz syndrome 4 (5)
-	-	5	not provided (6)
-	1	3	Familial thoracic aortic aneurysm and aortic dissection (4)
-	-	3	not specified (3)
-	-	1	Ehlers-Danlos syndrome (1)
-	-	1	Holt-Oram syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	1.7	L
PhyloP100		7.7
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.99	N
REVEL	Benign	0.22
Sift	Benign	0.048	D
Sift4G	Benign	0.32	T
Polyphen		0.39	B
Vest4		0.73
MVP		0.82
MPC		0.98
ClinPred		0.013	T
GERP RS		5.9
Varity_R		0.13
gMVP		0.76
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs10482810; hg19: chr1-218607532;