chr2-229768687-C-T

Position:

• chr2-229768687-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001348323.3(TRIP12):​c.5936G>A​(p.Ser1979Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TRIP12 NM_001348323.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.51

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TRIP12. . Gene score misZ 4.6402 (greater than the threshold 3.09). Trascript score misZ 6.3495 (greater than threshold 3.09). GenCC has associacion of gene with syndromic intellectual disability, Clark-Baraitser syndrome, complex neurodevelopmental disorder.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRIP12	NM_001348323.3	c.5936G>A	p.Ser1979Asn	missense_variant	41/42	ENST00000675903.1	NP_001335252.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRIP12	ENST00000675903.1	c.5936G>A	p.Ser1979Asn	missense_variant	41/42		NM_001348323.3	ENSP00000502713.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 05, 2019

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T;.;.;T
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.89	D;D;D;D
M_CAP	Uncertain	0.093	D
MetaRNN	Uncertain	0.51	D;D;D;D
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	1.6	L;.;.;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-2.3	N;N;N;N
REVEL	Benign	0.21
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.014	D;D;D;.
Polyphen		0.98	D;.;.;.
Vest4		0.65
MutPred		0.39		Loss of disorder (P = 0.1511);.;.;.;
MVP		0.41
MPC		2.2
ClinPred		0.88	D
GERP RS		5.9
Varity_R		0.53
gMVP		0.87

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-230633403;