NM_145307.4:c.1385A>C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_145307.4(RTKN2):​c.1385A>C​(p.His462Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,018 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H462R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000027 (0 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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09122774).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RTKN2	NM_145307.4	c.1385A>C	p.His462Pro	missense_variant	Exon 12 of 12	ENST00000373789.8	NP_660350.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RTKN2	ENST00000373789.8	c.1385A>C	p.His462Pro	missense_variant	Exon 12 of 12	1	NM_145307.4	ENSP00000362894.3
RTKN2	ENST00000315289.6	c.791A>C	p.His264Pro	missense_variant	Exon 8 of 9	2		ENSP00000325379.2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250568 Hom.: 0 AF XY: 0.0000222 AC XY: 3 AN XY: 135396

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461018 Hom.: 0 Cov.: 41 AF XY: 0.00000550 AC XY: 4 AN XY: 726776

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	4.3
DANN	Benign	0.90
DEOGEN2	Benign	0.0090	.;T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.73	T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.091	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.9	.;M
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.77	N;N
REVEL	Benign	0.018
Sift	Benign	0.14	T;T
Sift4G	Benign	0.19	T;T
Polyphen		0.26	B;B
Vest4		0.33
MutPred		0.18		.;Gain of glycosylation at H462 (P = 0.0722);
MVP		0.36
MPC		0.068
ClinPred		0.049	T
GERP RS		2.3
Varity_R		0.13
gMVP		0.22

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;