rs3125734

Positions:

• chr10-62198353-T-C
• chr10-62198353-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_145307.4(RTKN2):​c.1385A>G​(p.His462Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.632 in 1,611,530 control chromosomes in the GnomAD database, including 327,762 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.57 (25934 hom., cov: 30)
  • Exomes 𝑓: 0.64 (301828 hom.)
• Consequence: RTKN2 NM_145307.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.65

Genes affected

RTKN2 (HGNC:19364): (rhotekin 2) Involved in negative regulation of intrinsic apoptotic signaling pathway; positive regulation of NF-kappaB transcription factor activity; and positive regulation of NIK/NF-kappaB signaling. Located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.7182744E-7).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.886 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RTKN2	NM_145307.4	c.1385A>G	p.His462Arg	missense_variant	12/12	ENST00000373789.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RTKN2	ENST00000373789.8	c.1385A>G	p.His462Arg	missense_variant	12/12	1	NM_145307.4	P1
RTKN2	ENST00000315289.6	c.791A>G	p.His264Arg	missense_variant	8/9	2

Frequencies

GnomAD3 genomes AF: 0.570 AC: 86523 AN: 151730 Hom.: 25940 Cov.: 30

Gnomad AFR AF: 0.381

Gnomad AMI AF: 0.515

Gnomad AMR AF: 0.667

Gnomad ASJ AF: 0.570

Gnomad EAS AF: 0.908

Gnomad SAS AF: 0.528

Gnomad FIN AF: 0.583

Gnomad MID AF: 0.595

Gnomad NFE AF: 0.639

Gnomad OTH AF: 0.603

GnomAD3 exomes AF: 0.646 AC: 161906 AN: 250568 Hom.: 54364 AF XY: 0.639 AC XY: 86577 AN XY: 135396

Gnomad AFR exome AF: 0.376

Gnomad AMR exome AF: 0.783

Gnomad ASJ exome AF: 0.580

Gnomad EAS exome AF: 0.918

Gnomad SAS exome AF: 0.536

Gnomad FIN exome AF: 0.599

Gnomad NFE exome AF: 0.644

Gnomad OTH exome AF: 0.635

GnomAD4 exome AF: 0.638 AC: 931479 AN: 1459682 Hom.: 301828 Cov.: 41 AF XY: 0.635 AC XY: 460937 AN XY: 726152

Gnomad4 AFR exome AF: 0.370

Gnomad4 AMR exome AF: 0.771

Gnomad4 ASJ exome AF: 0.585

Gnomad4 EAS exome AF: 0.903

Gnomad4 SAS exome AF: 0.536

Gnomad4 FIN exome AF: 0.597

Gnomad4 NFE exome AF: 0.643

Gnomad4 OTH exome AF: 0.626

GnomAD4 genome AF: 0.570 AC: 86531 AN: 151848 Hom.: 25934 Cov.: 30 AF XY: 0.569 AC XY: 42222 AN XY: 74186

Gnomad4 AFR AF: 0.380

Gnomad4 AMR AF: 0.667

Gnomad4 ASJ AF: 0.570

Gnomad4 EAS AF: 0.908

Gnomad4 SAS AF: 0.527

Gnomad4 FIN AF: 0.583

Gnomad4 NFE AF: 0.639

Gnomad4 OTH AF: 0.600

Alfa AF: 0.639 Hom.: 77223

Bravo AF: 0.576

TwinsUK AF: 0.645 AC: 2393

ALSPAC AF: 0.645 AC: 2486

ESP6500AA AF: 0.383 AC: 1687

ESP6500EA AF: 0.641 AC: 5514

ExAC AF: 0.634 AC: 76945

Asia WGS AF: 0.699 AC: 2431 AN: 3478

EpiCase AF: 0.645

EpiControl AF: 0.640

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	2.1
DANN	Benign	0.70
DEOGEN2	Benign	0.0049	.;T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.49	T;T
MetaRNN	Benign	7.7e-7	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	.;M
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.080	N;N
REVEL	Benign	0.045
Sift	Benign	0.23	T;T
Sift4G	Benign	0.46	T;T
Polyphen		0.0010	B;B
Vest4		0.054
MPC		0.044
ClinPred		0.0036	T
GERP RS		2.3
Varity_R		0.044
gMVP		0.11

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

Publications

LitVar

Other links and lift over

dbSNP: rs3125734; hg19: chr10-63958112;