2-229785841-TC-CT

Variant names:

• chr2-229785841-TC-CT
• NM_001348323.3:c.5009_5010delGAinsAG
• TRIP12 p.Arg1670Gln

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PS1 PM1

The NM_001348323.3(TRIP12):​c.5009_5010delGAinsAG​(p.Arg1670Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TRIP12 NM_001348323.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.51
• Publications: 0 publications found

Genes affected

TRIP12 (HGNC:12306): (thyroid hormone receptor interactor 12) The protein encoded by this gene is an E3 ubiquitin-protein ligase involved in the degradation of the p19ARF/ARF isoform of CDKN2A, a tumor suppressor. The encoded protein also plays a role in the DNA damage response by regulating the stability of USP7, which regulates tumor suppressor p53. [provided by RefSeq, Jan 2017]

TRIP12 Gene-Disease associations (from GenCC):

• Clark-Baraitser syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PS1: Transcript NM_001348323.3 (TRIP12) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001348323.3

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001348323.3. 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
	TRIP12	NM_001348323.3	MANE Select	c.5009_5010delGAinsAG	p.Arg1670Gln	missense	N/A	NP_001335252.1	A0A6Q8PHK0
	TRIP12	NM_001348328.1		c.5012_5013delGAinsAG	p.Arg1671Gln	missense	N/A	NP_001335257.1	A0A6Q8PGG9
	TRIP12	NM_001348329.2		c.5012_5013delGAinsAG	p.Arg1671Gln	missense	N/A	NP_001335258.1	A0A6Q8PGG9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIP12	ENST00000675903.1	MANE Select	c.5009_5010delGAinsAG	p.Arg1670Gln	missense	N/A	ENSP00000502713.1	A0A6Q8PHK0
	TRIP12	ENST00000389044.8	TSL:1	c.4928_4929delGAinsAG	p.Arg1643Gln	missense	N/A	ENSP00000373696.4	Q14669-3
	TRIP12	ENST00000283943.9	TSL:1	c.4784_4785delGAinsAG	p.Arg1595Gln	missense	N/A	ENSP00000283943.4	Q14669-1

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.5

Splicing

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

hg19: chr2-230650557;