NM_145307.4:c.1085A>T

Variant names:

• chr10-62204958-T-A
• rs141013908
• NM_145307.4:c.1085A>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_145307.4(RTKN2):​c.1085A>T​(p.Asn362Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000069 in 1,449,586 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N362S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RTKN2 NM_145307.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.78
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.865

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.1085A>T	p.Asn362Ile	missense	Exon 10 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.1085A>T	p.Asn362Ile	missense	Exon 10 of 12	ENSP00000362894.3	Q8IZC4-1
	RTKN2	ENST00000955691.1		c.1190A>T	p.Asn397Ile	missense	Exon 12 of 14	ENSP00000625750.1
	RTKN2	ENST00000919899.1		c.1148A>T	p.Asn383Ile	missense	Exon 11 of 13	ENSP00000589958.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000420 AC: 1 AN: 238362 AF XY: 0.00000774

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: 6.90e-7 AC: 1 AN: 1449586 Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1 AN XY: 720628

African (AFR) AF: 0.00 AC: 0 AN: 32610

American (AMR) AF: 0.00 AC: 0 AN: 42424

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25962

East Asian (EAS) AF: 0.00 AC: 0 AN: 38866

South Asian (SAS) AF: 0.0000121 AC: 1 AN: 82840

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53314

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107878

Other (OTH) AF: 0.00 AC: 0 AN: 59954

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.014	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.66	D
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		3.8
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.63		Loss of catalytic residue at N362 (P = 0.0543)
MVP		0.69
MPC		0.30
ClinPred		0.99	D
GERP RS		2.7
Varity_R		0.80
gMVP		0.75
Mutation Taster		=34/66	disease causing

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: rs141013908; hg19: chr10-63964717;