16-88714227-GGTGT-G

Variant names:

• chr16-88714227-GGTGT-G
• rs149847195
• NM_001012759.3:c.1097+2_1097+5delTGTG

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

The NM_001012759.3(CTU2):​c.1097+2_1097+5delTGTG variant causes a splice donor, splice region, intron change. 1/1 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 0)
• Consequence: CTU2 NM_001012759.3 splice_donor, splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.54
• Publications: 4 publications found

Genes affected

CTU2 (HGNC:28005): (cytosolic thiouridylase subunit 2) This gene encodes a protein which is involved in the post-transcriptional modification of transfer RNAs (tRNAs). The encoded protein plays a role in thiolation of uridine residue present at the wobble position in a subset of tRNAs, resulting in enhanced codon reading accuracy. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jan 2016]

CTU2 Gene-Disease associations (from GenCC):

• microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 3.1, offset of 2, new splice context is: gggGTgtgt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001012759.3. 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
	CTU2	NM_001012759.3	MANE Select	c.1097+2_1097+5delTGTG		splice_donor splice_region intron	N/A	NP_001012777.1	Q2VPK5-1
	CTU2	NM_001318507.2		c.1310+2_1310+5delTGTG		splice_donor splice_region intron	N/A	NP_001305436.1	H3BSW6
	CTU2	NM_001012762.3		c.1097+2_1097+5delTGTG		splice_donor splice_region intron	N/A	NP_001012780.1	Q2VPK5-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTU2	ENST00000453996.7	TSL:1 MANE Select	c.1097+1_1097+4delGTGT		splice_donor splice_region intron	N/A	ENSP00000388320.2	Q2VPK5-1
	CTU2	ENST00000567949.5	TSL:1	c.1310+1_1310+4delGTGT		splice_donor splice_region intron	N/A	ENSP00000456908.1	H3BSW6
	CTU2	ENST00000564105.5	TSL:1	n.*808+1_*808+4delGTGT		splice_donor splice_region intron	N/A	ENSP00000454923.1	H3BNM3

Frequencies

GnomAD3 genomes Cov.: 0

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

GnomAD4 genome Cov.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.63		Position offset: 6
DS_DL_spliceai		0.95		Position offset: 0

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs149847195; hg19: chr16-88780635;