chr10-62199778-C-T

Variant names:

• chr10-62199778-C-T
• rs1564498631
• NM_145307.4:c.1270G>A

Variant summary

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

The NM_145307.4(RTKN2):​c.1270G>A​(p.Ala424Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,459,874 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RTKN2 NM_145307.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.54
• Publications: 0 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1270G>A	p.Ala424Thr	missense	Exon 11 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.1270G>A	p.Ala424Thr	missense	Exon 11 of 12	ENSP00000362894.3	Q8IZC4-1
	RTKN2	ENST00000955691.1		c.1375G>A	p.Ala459Thr	missense	Exon 13 of 14	ENSP00000625750.1
	RTKN2	ENST00000919899.1		c.1333G>A	p.Ala445Thr	missense	Exon 12 of 13	ENSP00000589958.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251198 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: 0.0000462

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459874 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 726424

African (AFR) AF: 0.00 AC: 0 AN: 33404

American (AMR) AF: 0.00 AC: 0 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39628

South Asian (SAS) AF: 0.00 AC: 0 AN: 86162

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110430

Other (OTH) AF: 0.00 AC: 0 AN: 60308

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

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	0.27
BayesDel_addAF	Benign	-0.070	T
BayesDel_noAF	Benign	-0.34
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.049	T
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.035	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Benign	-0.60	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		5.5
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.091
Sift	Uncertain	0.026	D
Sift4G	Uncertain	0.030	D
Polyphen		1.0	D
Vest4		0.69
MutPred		0.20		Gain of disorder (P = 0.0401)
MVP		0.56
MPC		0.27
ClinPred		0.97	D
GERP RS		4.8
Varity_R		0.25
gMVP		0.48
Mutation Taster		=72/28	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: rs1564498631; hg19: chr10-63959537;