rs2739206

Variant names:

• chr4-110633553-G-C
• rs2739206
• ENST00000355080.9:c.-10-545C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000355080.9(PITX2):​c.-10-545C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.626 in 151,900 control chromosomes in the GnomAD database, including 30,335 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.63 (30335 hom., cov: 31)
• Consequence: PITX2 ENST00000355080.9 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.383
• Publications: 4 publications found

Genes affected

PITX2 (HGNC:9005): (paired like homeodomain 2) This gene encodes a member of the RIEG/PITX homeobox family, which is in the bicoid class of homeodomain proteins. The encoded protein acts as a transcription factor and regulates procollagen lysyl hydroxylase gene expression. This protein plays a role in the terminal differentiation of somatotroph and lactotroph cell phenotypes, is involved in the development of the eye, tooth and abdominal organs, and acts as a transcriptional regulator involved in basal and hormone-regulated activity of prolactin. Mutations in this gene are associated with Axenfeld-Rieger syndrome, iridogoniodysgenesis syndrome, and sporadic cases of Peters anomaly. A similar protein in other vertebrates is involved in the determination of left-right asymmetry during development. Alternatively spliced transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Jul 2008]

PITX2 Gene-Disease associations (from GenCC):

• anterior segment dysgenesis 4

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• Axenfeld-Rieger syndrome type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• ring dermoid of cornea

  Inheritance: Unknown, AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• aniridia

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• Axenfeld anomaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Axenfeld-Rieger syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial atrial fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Rieger anomaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Peters anomaly

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.679 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PITX2	NM_001204397.2	c.-10-545C>G		intron_variant	Intron 2 of 5		NP_001191326.1
PITX2	NM_001204398.1	c.-10-545C>G		intron_variant	Intron 1 of 4		NP_001191327.1
PITX2	NM_153426.3	c.-10-545C>G		intron_variant	Intron 1 of 4		NP_700475.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PITX2	ENST00000355080.9	c.-10-545C>G		intron_variant	Intron 1 of 3	1		ENSP00000347192.5
PITX2	ENST00000354925.6	c.-10-545C>G		intron_variant	Intron 3 of 6	2		ENSP00000347004.2
PITX2	ENST00000394595.8	c.-10-545C>G		intron_variant	Intron 1 of 4	5		ENSP00000378095.4

Frequencies

GnomAD3 genomes AF: 0.626 AC: 95058 AN: 151780 Hom.: 30305 Cov.: 31

Gnomad AFR AF: 0.523

Gnomad AMI AF: 0.763

Gnomad AMR AF: 0.685

Gnomad ASJ AF: 0.716

Gnomad EAS AF: 0.494

Gnomad SAS AF: 0.678

Gnomad FIN AF: 0.570

Gnomad MID AF: 0.715

Gnomad NFE AF: 0.684

Gnomad OTH AF: 0.633

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.626 AC: 95140 AN: 151900 Hom.: 30335 Cov.: 31 AF XY: 0.621 AC XY: 46043 AN XY: 74202

African (AFR) AF: 0.523 AC: 21662 AN: 41414

American (AMR) AF: 0.685 AC: 10469 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.716 AC: 2484 AN: 3470

East Asian (EAS) AF: 0.494 AC: 2544 AN: 5152

South Asian (SAS) AF: 0.679 AC: 3258 AN: 4798

European-Finnish (FIN) AF: 0.570 AC: 5998 AN: 10532

Middle Eastern (MID) AF: 0.714 AC: 210 AN: 294

European-Non Finnish (NFE) AF: 0.684 AC: 46473 AN: 67944

Other (OTH) AF: 0.638 AC: 1346 AN: 2110

Alfa AF: 0.627 Hom.: 3748

Bravo AF: 0.633

Asia WGS AF: 0.563 AC: 1958 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	6.5
DANN	Benign	0.56
PhyloP100		-0.38
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs2739206; hg19: chr4-111554709;