14-21031056-C-T

Position:

• chr14-21031056-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_173846.5(TPPP2):​c.218C>T​(p.Ala73Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TPPP2 NM_173846.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.67

Genes affected

TPPP2 (HGNC:19293): (tubulin polymerization promoting protein family member 2) Enables tubulin binding activity. Involved in regulation of flagellated sperm motility. Located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

NDRG2 (HGNC:14460): (NDRG family member 2) This gene is a member of the N-myc downregulated gene family which belongs to the alpha/beta hydrolase superfamily. The protein encoded by this gene is a cytoplasmic protein that may play a role in neurite outgrowth. This gene may be involved in glioblastoma carcinogenesis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.803

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPPP2	NM_173846.5	c.218C>T	p.Ala73Val	missense_variant	3/4	ENST00000321760.11	NP_776245.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPPP2	ENST00000321760.11	c.218C>T	p.Ala73Val	missense_variant	3/4	1	NM_173846.5	ENSP00000317595.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 13, 2021

The c.218C>T (p.A73V) alteration is located in exon 3 (coding exon 2) of the TPPP2 gene. This alteration results from a C to T substitution at nucleotide position 218, causing the alanine (A) at amino acid position 73 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.076	T;.;T;.;T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	.;D;T;D;D
M_CAP	Benign	0.019	T
MetaRNN	Pathogenic	0.80	D;D;D;D;D
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Uncertain	2.3	M;.;M;.;.
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-3.4	D;D;D;D;D
REVEL	Benign	0.27
Sift	Benign	0.12	T;D;T;D;D
Sift4G	Benign	0.15	T;D;T;D;D
Polyphen		0.93	P;.;P;.;.
Vest4		0.85
MutPred		0.71		Loss of ubiquitination at K75 (P = 0.0825);Loss of ubiquitination at K75 (P = 0.0825);Loss of ubiquitination at K75 (P = 0.0825);Loss of ubiquitination at K75 (P = 0.0825);.;
MVP		0.33
MPC		0.19
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.44
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1248364322; hg19: chr14-21499215; COSMIC: COSV58794343; COSMIC: COSV58794343;