chr14-21031962-G-T

Variant names:

• chr14-21031962-G-T
• rs9624
• NM_173846.5:c.398G>T

Variant summary

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

The NM_173846.5(TPPP2):​c.398G>T​(p.Arg133Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.136 in 1,613,990 control chromosomes in the GnomAD database, including 16,915 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R133C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.11 (1293 hom., cov: 32)
  • Exomes 𝑓: 0.14 (15622 hom.)
• Consequence: TPPP2 NM_173846.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.15
• Publications: 25 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0031427443).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.271 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPPP2	NM_173846.5	c.398G>T	p.Arg133Leu	missense_variant	Exon 4 of 4	ENST00000321760.11	NP_776245.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPPP2	ENST00000321760.11	c.398G>T	p.Arg133Leu	missense_variant	Exon 4 of 4	1	NM_173846.5	ENSP00000317595.6

Frequencies

GnomAD3 genomes AF: 0.114 AC: 17308 AN: 152048 Hom.: 1291 Cov.: 32

Gnomad AFR AF: 0.0409

Gnomad AMI AF: 0.125

Gnomad AMR AF: 0.187

Gnomad ASJ AF: 0.0986

Gnomad EAS AF: 0.283

Gnomad SAS AF: 0.181

Gnomad FIN AF: 0.0786

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.130

Gnomad OTH AF: 0.119

GnomAD2 exomes AF: 0.152 AC: 38245 AN: 251416 AF XY: 0.153

Gnomad AFR exome AF: 0.0383

Gnomad AMR exome AF: 0.238

Gnomad ASJ exome AF: 0.109

Gnomad EAS exome AF: 0.290

Gnomad FIN exome AF: 0.0753

Gnomad NFE exome AF: 0.130

Gnomad OTH exome AF: 0.137

GnomAD4 exome AF: 0.139 AC: 202848 AN: 1461824 Hom.: 15622 Cov.: 32 AF XY: 0.140 AC XY: 101810 AN XY: 727212

African (AFR) AF: 0.0362 AC: 1211 AN: 33480

American (AMR) AF: 0.232 AC: 10365 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 2829 AN: 26134

East Asian (EAS) AF: 0.283 AC: 11230 AN: 39696

South Asian (SAS) AF: 0.181 AC: 15599 AN: 86250

European-Finnish (FIN) AF: 0.0779 AC: 4160 AN: 53420

Middle Eastern (MID) AF: 0.112 AC: 646 AN: 5768

European-Non Finnish (NFE) AF: 0.134 AC: 148802 AN: 1111966

Other (OTH) AF: 0.133 AC: 8006 AN: 60390

GnomAD4 genome AF: 0.114 AC: 17306 AN: 152166 Hom.: 1293 Cov.: 32 AF XY: 0.116 AC XY: 8596 AN XY: 74402

African (AFR) AF: 0.0409 AC: 1697 AN: 41534

American (AMR) AF: 0.187 AC: 2857 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0986 AC: 342 AN: 3468

East Asian (EAS) AF: 0.283 AC: 1460 AN: 5160

South Asian (SAS) AF: 0.181 AC: 870 AN: 4816

European-Finnish (FIN) AF: 0.0786 AC: 833 AN: 10600

Middle Eastern (MID) AF: 0.139 AC: 41 AN: 294

European-Non Finnish (NFE) AF: 0.130 AC: 8837 AN: 67982

Other (OTH) AF: 0.121 AC: 255 AN: 2114

Alfa AF: 0.128 Hom.: 4512

Bravo AF: 0.119

TwinsUK AF: 0.130 AC: 483

ALSPAC AF: 0.140 AC: 539

ESP6500AA AF: 0.0363 AC: 160

ESP6500EA AF: 0.127 AC: 1088

ExAC AF: 0.148 AC: 18021

EpiCase AF: 0.126

EpiControl AF: 0.125

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T;T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	.;D
MetaRNN	Benign	0.0031	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.2	M;M
PhyloP100		8.1
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-5.9	D;D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0090	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;D
Vest4		0.38
MPC		0.20
ClinPred		0.038	T
GERP RS		3.6
Varity_R		0.61
gMVP		0.47
Mutation Taster		=88/12	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: rs9624; hg19: chr14-21500121; COSMIC: COSV58794325; COSMIC: COSV58794325;