14-21030729-G-T

Variant names:

• chr14-21030729-G-T
• rs149482997
• NM_173846.5:c.148G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_173846.5(TPPP2):​c.148G>T​(p.Val50Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,818 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V50M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TPPP2 NM_173846.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.04
• Publications: 0 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.148G>T	p.Val50Leu	missense	Exon 2 of 4	NP_776245.2	P59282
	NDRG2	NM_001282211.2		c.25-7408C>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.148G>T	p.Val50Leu	missense	Exon 2 of 4	ENSP00000317595.6	P59282
	TPPP2	ENST00000534434.2	TSL:1	n.336G>T		non_coding_transcript_exon	Exon 2 of 3
	TPPP2	ENST00000530140.6	TSL:2	c.148G>T	p.Val50Leu	missense	Exon 2 of 4	ENSP00000435356.2	P59282

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461818 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727210

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111984

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.017	T
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.043	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Benign	-0.73	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		5.0
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.27
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.045	D
Polyphen		0.43	B
Vest4		0.67
MutPred		0.68		Gain of catalytic residue at V50 (P = 0.0611)
MVP		0.12
MPC		0.095
ClinPred		0.98	D
GERP RS		4.5
PromoterAI		-0.042	Neutral
Varity_R		0.31
gMVP		0.77
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs149482997; hg19: chr14-21498888;