10-62197946-T-A

Variant names:

• chr10-62197946-T-A
• rs148375207
• NM_145307.4:c.1792A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_145307.4(RTKN2):​c.1792A>T​(p.Ile598Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,668 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I598V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RTKN2 NM_145307.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.75
• Publications: 1 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11334762).

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.1792A>T	p.Ile598Phe	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.1792A>T	p.Ile598Phe	missense	Exon 12 of 12	ENSP00000362894.3	Q8IZC4-1
	RTKN2	ENST00000955691.1		c.1897A>T	p.Ile633Phe	missense	Exon 14 of 14	ENSP00000625750.1
	RTKN2	ENST00000919899.1		c.1855A>T	p.Ile619Phe	missense	Exon 13 of 13	ENSP00000589958.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251000 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461668 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727138

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111886

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

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	15
DANN	Benign	0.95
DEOGEN2	Benign	0.022	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		1.8
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.15
Sift	Benign	0.055	T
Sift4G	Benign	0.22	T
Polyphen		0.15	B
Vest4		0.27
MutPred		0.14		Gain of ubiquitination at K596 (P = 0.078)
MVP		0.15
MPC		0.076
ClinPred		0.28	T
GERP RS		1.8
Varity_R		0.046
gMVP		0.18
Mutation Taster		=91/9	polymorphism

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: rs148375207; hg19: chr10-63957705;