rs3125734

Variant names:

• chr10-62198353-T-C
• rs3125734
• NM_145307.4:c.1385A>G
• RTKN2 p.His462Arg

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 54 publications found

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]

RTKN2 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145307.4. 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
	RTKN2	NM_145307.4	MANE Select	c.1385A>G	p.His462Arg	missense	Exon 12 of 12	NP_660350.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTKN2	ENST00000373789.8	TSL:1 MANE Select	c.1385A>G	p.His462Arg	missense	Exon 12 of 12	ENSP00000362894.3	Q8IZC4-1
	RTKN2	ENST00000955691.1		c.1490A>G	p.His497Arg	missense	Exon 14 of 14	ENSP00000625750.1
	RTKN2	ENST00000919899.1		c.1448A>G	p.His483Arg	missense	Exon 13 of 13	ENSP00000589958.1

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

GnomAD2 exomes AF: 0.646 AC: 161906 AN: 250568 AF XY: 0.639

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 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

African (AFR) AF: 0.370 AC: 12345 AN: 33392

American (AMR) AF: 0.771 AC: 34394 AN: 44590

Ashkenazi Jewish (ASJ) AF: 0.585 AC: 15275 AN: 26100

East Asian (EAS) AF: 0.903 AC: 35818 AN: 39686

South Asian (SAS) AF: 0.536 AC: 46089 AN: 86044

European-Finnish (FIN) AF: 0.597 AC: 31846 AN: 53346

Middle Eastern (MID) AF: 0.603 AC: 3476 AN: 5766

European-Non Finnish (NFE) AF: 0.643 AC: 714502 AN: 1110432

Other (OTH) AF: 0.626 AC: 37734 AN: 60326

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

African (AFR) AF: 0.380 AC: 15734 AN: 41396

American (AMR) AF: 0.667 AC: 10161 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.570 AC: 1975 AN: 3462

East Asian (EAS) AF: 0.908 AC: 4702 AN: 5180

South Asian (SAS) AF: 0.527 AC: 2534 AN: 4808

European-Finnish (FIN) AF: 0.583 AC: 6136 AN: 10528

Middle Eastern (MID) AF: 0.602 AC: 177 AN: 294

European-Non Finnish (NFE) AF: 0.639 AC: 43381 AN: 67930

Other (OTH) AF: 0.600 AC: 1262 AN: 2102

Alfa AF: 0.629 Hom.: 147624

Bravo AF: 0.576

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 v4.9

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
MetaRNN	Benign	7.7e-7	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	M
PhyloP100		1.7
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.080	N
REVEL	Benign	0.045
Sift	Benign	0.23	T
Sift4G	Benign	0.46	T
Varity_R		0.044
gMVP		0.11
Mutation Taster		=96/4	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs3125734;

hg19: chr10-63958112;

COSMIC: COSV107318967;