rs2595110

Variant names:

• chr4-110624167-A-G
• rs2595110
• ENST00000355080.9:c.47-2798T>C

Your query was ambiguous. Multiple possible variants found:

• chr4-110624167-A-G
• chr4-110624167-A-T

Variant summary

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

The ENST00000355080.9(PITX2):​c.47-2798T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.226 in 152,108 control chromosomes in the GnomAD database, including 4,642 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 0.23 (4642 hom., cov: 32)
• Consequence: PITX2 ENST00000355080.9 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.558
• Publications: 10 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=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.301 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PITX2	NM_001204397.2	c.185-2798T>C		intron_variant	Intron 4 of 5		NP_001191326.1
PITX2	NM_001204398.1	c.185-2798T>C		intron_variant	Intron 3 of 4		NP_001191327.1
PITX2	NM_153426.3	c.185-2798T>C		intron_variant	Intron 3 of 4		NP_700475.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PITX2	ENST00000355080.9	c.47-2798T>C		intron_variant	Intron 2 of 3	1		ENSP00000347192.5
PITX2	ENST00000354925.6	c.185-2798T>C		intron_variant	Intron 5 of 6	2		ENSP00000347004.2
PITX2	ENST00000394595.8	c.185-2798T>C		intron_variant	Intron 3 of 4	5		ENSP00000378095.4

Frequencies

GnomAD3 genomes AF: 0.226 AC: 34399 AN: 151990 Hom.: 4638 Cov.: 32

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.545

Gnomad AMR AF: 0.183

Gnomad ASJ AF: 0.216

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.256

Gnomad FIN AF: 0.329

Gnomad MID AF: 0.297

Gnomad NFE AF: 0.304

Gnomad OTH AF: 0.244

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

GnomAD4 genome AF: 0.226 AC: 34403 AN: 152108 Hom.: 4642 Cov.: 32 AF XY: 0.223 AC XY: 16590 AN XY: 74354

African (AFR) AF: 0.105 AC: 4356 AN: 41510

American (AMR) AF: 0.183 AC: 2800 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.216 AC: 751 AN: 3472

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5184

South Asian (SAS) AF: 0.256 AC: 1231 AN: 4814

European-Finnish (FIN) AF: 0.329 AC: 3468 AN: 10548

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.304 AC: 20691 AN: 67968

Other (OTH) AF: 0.242 AC: 510 AN: 2110

Alfa AF: 0.273 Hom.: 11624

Bravo AF: 0.211

Asia WGS AF: 0.110 AC: 381 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	14
DANN	Benign	0.65
PhyloP100		0.56
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: rs2595110; hg19: chr4-111545323; COSMIC: COSV60740006; COSMIC: COSV60740006;