chr2-73729997-A-G

Variant names:

• chr2-73729997-A-G
• rs7210
• NM_016058.5:c.474T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_016058.5(TPRKB):​c.474T>C​(p.Ile158Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.639 in 1,566,616 control chromosomes in the GnomAD database, including 324,466 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (26579 hom., cov: 32)
  • Exomes 𝑓: 0.65 (297887 hom.)
• Consequence: TPRKB NM_016058.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.754
• Publications: 21 publications found

Genes affected

TPRKB (HGNC:24259): (TP53RK binding protein) Enables protein kinase binding activity. Involved in tRNA threonylcarbamoyladenosine modification. Located in cytosol and nucleus. Part of EKC/KEOPS complex. Implicated in Galloway-Mowat syndrome 5. [provided by Alliance of Genome Resources, Apr 2022]

TPRKB Gene-Disease associations (from GenCC):

• Galloway-Mowat syndrome 5

  Inheritance: AR, Unknown Classification: STRONG, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia
• Galloway-Mowat syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 2-73729997-A-G is Benign according to our data. Variant chr2-73729997-A-G is described in ClinVar as Benign. ClinVar VariationId is 1253010.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.754 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.678 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016058.5. 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
	TPRKB	NM_016058.5	MANE Select	c.474T>C	p.Ile158Ile	synonymous	Exon 5 of 5	NP_057142.1	Q9Y3C4-1
	TPRKB	NM_001330386.2		c.591T>C	p.Ile197Ile	synonymous	Exon 6 of 6	NP_001317315.1	Q9Y3C4-3
	TPRKB	NM_001330387.2		c.591T>C	p.Ile197Ile	synonymous	Exon 6 of 6	NP_001317316.1	Q9Y3C4-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPRKB	ENST00000272424.11	TSL:1 MANE Select	c.474T>C	p.Ile158Ile	synonymous	Exon 5 of 5	ENSP00000272424.5	Q9Y3C4-1
	TPRKB	ENST00000318190.7	TSL:5	c.591T>C	p.Ile197Ile	synonymous	Exon 6 of 6	ENSP00000325398.7	Q9Y3C4-3
	TPRKB	ENST00000409716.6	TSL:5	c.591T>C	p.Ile197Ile	synonymous	Exon 6 of 6	ENSP00000386936.2	Q9Y3C4-3

Frequencies

GnomAD3 genomes AF: 0.576 AC: 87527 AN: 151940 Hom.: 26572 Cov.: 32

Gnomad AFR AF: 0.365

Gnomad AMI AF: 0.724

Gnomad AMR AF: 0.586

Gnomad ASJ AF: 0.641

Gnomad EAS AF: 0.697

Gnomad SAS AF: 0.676

Gnomad FIN AF: 0.706

Gnomad MID AF: 0.674

Gnomad NFE AF: 0.659

Gnomad OTH AF: 0.604

GnomAD2 exomes AF: 0.628 AC: 140375 AN: 223410 AF XY: 0.637

Gnomad AFR exome AF: 0.349

Gnomad AMR exome AF: 0.541

Gnomad ASJ exome AF: 0.647

Gnomad EAS exome AF: 0.703

Gnomad FIN exome AF: 0.695

Gnomad NFE exome AF: 0.653

Gnomad OTH exome AF: 0.642

GnomAD4 exome AF: 0.646 AC: 913885 AN: 1414558 Hom.: 297887 Cov.: 33 AF XY: 0.647 AC XY: 454507 AN XY: 702184

African (AFR) AF: 0.349 AC: 11264 AN: 32280

American (AMR) AF: 0.543 AC: 20644 AN: 37984

Ashkenazi Jewish (ASJ) AF: 0.651 AC: 16000 AN: 24590

East Asian (EAS) AF: 0.681 AC: 26209 AN: 38474

South Asian (SAS) AF: 0.668 AC: 54092 AN: 80946

European-Finnish (FIN) AF: 0.697 AC: 35912 AN: 51508

Middle Eastern (MID) AF: 0.635 AC: 3570 AN: 5622

European-Non Finnish (NFE) AF: 0.653 AC: 708511 AN: 1084882

Other (OTH) AF: 0.647 AC: 37683 AN: 58272

GnomAD4 genome AF: 0.576 AC: 87572 AN: 152058 Hom.: 26579 Cov.: 32 AF XY: 0.582 AC XY: 43266 AN XY: 74330

African (AFR) AF: 0.365 AC: 15151 AN: 41474

American (AMR) AF: 0.585 AC: 8937 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.641 AC: 2222 AN: 3468

East Asian (EAS) AF: 0.697 AC: 3611 AN: 5182

South Asian (SAS) AF: 0.676 AC: 3257 AN: 4818

European-Finnish (FIN) AF: 0.706 AC: 7463 AN: 10568

Middle Eastern (MID) AF: 0.677 AC: 199 AN: 294

European-Non Finnish (NFE) AF: 0.659 AC: 44798 AN: 67958

Other (OTH) AF: 0.604 AC: 1274 AN: 2110

Alfa AF: 0.637 Hom.: 52149

Bravo AF: 0.556

Asia WGS AF: 0.675 AC: 2348 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Galloway-Mowat syndrome 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	8.6
DANN	Benign	0.77
PhyloP100		0.75
Mutation Taster		=100/0	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: rs7210; hg19: chr2-73957124; COSMIC: COSV55541895; COSMIC: COSV55541895;