chr1-218434190-G-C

Position:

• chr1-218434190-G-C

Variant summary

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

The ENST00000366930.9(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. V207I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0034 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0051 (34 hom.)
• Consequence: TGFB2 ENST00000366930.9 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:2 B:17 O:1
• Conservation: PhyloP100: 7.75

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 155837.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-218434190-G-C is described in Lovd as [Likely_benign]. Variant chr1-218434190-G-C is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 517 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGFB2	NM_003238.6	c.619G>C	p.Val207Leu	missense_variant	3/7	ENST00000366930.9	NP_003229.1
TGFB2	NM_001135599.4	c.703G>C	p.Val235Leu	missense_variant	4/8		NP_001129071.1
TGFB2	NR_138148.2	n.1985G>C		non_coding_transcript_exon_variant	3/7
TGFB2	NR_138149.2	n.2069G>C		non_coding_transcript_exon_variant	4/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGFB2	ENST00000366930.9	c.619G>C	p.Val207Leu	missense_variant	3/7	1	NM_003238.6	ENSP00000355897	P1
TGFB2	ENST00000366929.4	c.703G>C	p.Val235Leu	missense_variant	4/8	1		ENSP00000355896
TGFB2	ENST00000479322.1	n.65G>C		non_coding_transcript_exon_variant	1/5	3
TGFB2	ENST00000488793.1	n.283G>C		non_coding_transcript_exon_variant	3/3	3

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

GnomAD3 exomes AF: 0.00330 AC: 828 AN: 251286 Hom.: 5 AF XY: 0.00342 AC XY: 465 AN XY: 135806

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 SAS exome AF: 0.00137

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

Gnomad4 AFR exome AF: 0.000806

Gnomad4 AMR exome AF: 0.00148

Gnomad4 ASJ exome AF: 0.00505

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00153

Gnomad4 FIN exome AF: 0.00367

Gnomad4 NFE exome AF: 0.00601

Gnomad4 OTH exome AF: 0.00452

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

Gnomad4 AFR AF: 0.00115

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.00548

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00330

Gnomad4 NFE AF: 0.00544

Gnomad4 OTH AF: 0.00473

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

Significance: Benign/Likely benign

Submissions summary: Uncertain:2 Benign:17 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5 Other:1

Likely benign, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 28, 2024	See Variant Classification Assertion Criteria. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 28, 2017	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant classified as Likely benign and reported on 07-21-2015 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	TGFB2: BS2 -

Loeys-Dietz syndrome 4 Uncertain:1 Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Uncertain significance, no assertion criteria provided	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Mar 30, 2016	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 21, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 16, 2019	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Uncertain significance, no assertion criteria provided	clinical testing	Blueprint Genetics	Oct 11, 2013	- -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Mar 20, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Aug 01, 2023	- -

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 29, 2017	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 12, 2019	Variant summary: TGFB2 c.619G>C (p.Val207Leu) results in a conservative amino acid change located in the TGF-beta propeptide domain (IPR001111) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0033 in 251286 control chromosomes, predominantly at a frequency of 0.005 within the Non-Finnish European subpopulation in the gnomAD database, including 5 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 400 fold of the estimated maximal expected allele frequency for a pathogenic variant in TGFB2 causing Aortopathy phenotype (1.3e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.619G>C has been reported in the literature in individuals affected with aortic root dilation, vascular anomalies and familial abdominal aortic aneurysm (Disha_2017, vandeLuijtgaarden_2015, Mattassi_2018) without strong evidence of causality. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (9x Likely benign/benign and 1x uncertain significance). Based on the evidence outlined above, the variant was classified as likely benign. -

Holt-Oram syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Ehlers-Danlos syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 25, 2022

- -

Computational scores

Source: dbNSFP v4.3

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;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.015	T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	1.7	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.99	N;N
REVEL	Benign	0.22
Sift	Benign	0.048	D;D
Sift4G	Benign	0.32	T;T
Polyphen		0.39	B;P
Vest4		0.73
MVP		0.82
MPC		0.98
ClinPred		0.013	T
GERP RS		5.9
Varity_R		0.13
gMVP		0.76

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

Publications

LitVar

Other links and lift over

dbSNP: rs10482810; hg19: chr1-218607532;