chr14-21031056-C-T

Variant names:

• chr14-21031056-C-T
• rs1248364322
• NM_173846.5:c.218C>T

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 2 publications found

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173846.5. 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
	TPPP2	NM_173846.5	MANE Select	c.218C>T	p.Ala73Val	missense	Exon 3 of 4	NP_776245.2	P59282
	NDRG2	NM_001282211.2		c.25-7735G>A		intron	N/A	NP_001269140.1	Q9UN36-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPPP2	ENST00000321760.11	TSL:1 MANE Select	c.218C>T	p.Ala73Val	missense	Exon 3 of 4	ENSP00000317595.6	P59282
	TPPP2	ENST00000534434.2	TSL:1	n.663C>T		non_coding_transcript_exon	Exon 2 of 3
	TPPP2	ENST00000530140.6	TSL:2	c.218C>T	p.Ala73Val	missense	Exon 3 of 4	ENSP00000435356.2	P59282

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.019	T
MetaRNN	Pathogenic	0.80	D
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		7.7
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.27
Sift	Benign	0.12	T
Sift4G	Benign	0.15	T
Polyphen		0.93	P
Vest4		0.85
MutPred		0.71		Loss of ubiquitination at K75 (P = 0.0825)
MVP		0.33
MPC		0.19
ClinPred		1.0	D
GERP RS		4.8
PromoterAI		-0.038	Neutral
Varity_R		0.44
gMVP		0.52
Mutation Taster		=61/39	polymorphism

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

Other links and lift over

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