2-229869365-C-T

Variant names:

• chr2-229869365-C-T
• rs475525
• NM_001348323.3:c.99-8834G>A

Variant summary

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

The NM_001348323.3(TRIP12):​c.99-8834G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.181 in 152,106 control chromosomes in the GnomAD database, including 2,728 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 0.18 (2728 hom., cov: 32)
• Consequence: TRIP12 NM_001348323.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.16
• Publications: 6 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: Labcorp Genetics (formerly Invitae), G2P
• complex neurodevelopmental disorder

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.269 is higher than 0.05.

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.99-8834G>A		intron	N/A	NP_001335252.1
	TRIP12	NM_001348328.1		c.99-8834G>A		intron	N/A	NP_001335257.1
	TRIP12	NM_001348329.2		c.99-8834G>A		intron	N/A	NP_001335258.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIP12	ENST00000675903.1	MANE Select	c.99-8834G>A		intron	N/A	ENSP00000502713.1
	TRIP12	ENST00000389044.8	TSL:1	c.99-8834G>A		intron	N/A	ENSP00000373696.4
	TRIP12	ENST00000283943.9	TSL:1	c.99-9791G>A		intron	N/A	ENSP00000283943.4

Frequencies

GnomAD3 genomes AF: 0.181 AC: 27478 AN: 151988 Hom.: 2721 Cov.: 32

Gnomad AFR AF: 0.112

Gnomad AMI AF: 0.333

Gnomad AMR AF: 0.158

Gnomad ASJ AF: 0.0995

Gnomad EAS AF: 0.281

Gnomad SAS AF: 0.241

Gnomad FIN AF: 0.171

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.220

Gnomad OTH AF: 0.154

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

GnomAD4 genome AF: 0.181 AC: 27504 AN: 152106 Hom.: 2728 Cov.: 32 AF XY: 0.179 AC XY: 13311 AN XY: 74338

African (AFR) AF: 0.112 AC: 4646 AN: 41518

American (AMR) AF: 0.159 AC: 2427 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.0995 AC: 345 AN: 3468

East Asian (EAS) AF: 0.281 AC: 1450 AN: 5164

South Asian (SAS) AF: 0.241 AC: 1162 AN: 4816

European-Finnish (FIN) AF: 0.171 AC: 1802 AN: 10560

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.220 AC: 14988 AN: 68000

Other (OTH) AF: 0.161 AC: 340 AN: 2108

Alfa AF: 0.176 Hom.: 1049

Bravo AF: 0.175

Asia WGS AF: 0.257 AC: 894 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.62
DANN	Benign	0.68
PhyloP100		-1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs475525; hg19: chr2-230734081; COSMIC: COSV107311611;