1-92324282-A-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_024813.3(RPAP2):c.1362A>C(p.Lys454Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000039 in 1,461,802 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000039 (0 hom.)
• Consequence: RPAP2 NM_024813.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.27

Genes affected

RPAP2 (HGNC:25791): (RNA polymerase II associated protein 2) Enables RNA polymerase II CTD heptapeptide repeat phosphatase activity. Involved in dephosphorylation of RNA polymerase II C-terminal domain and snRNA transcription. Located in cytosol and nucleolus. Part of RNA polymerase II, holoenzyme. [provided by Alliance of Genome Resources, Apr 2022]

GLMN (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06457496).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPAP2	NM_024813.3	c.1362A>C	p.Lys454Asn	missense_variant	8/13	ENST00000610020.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPAP2	ENST00000610020.2	c.1362A>C	p.Lys454Asn	missense_variant	8/13	1	NM_024813.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000200 AC: 5 AN: 250084 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135558

Gnomad AFR exome AF: 0.0000639

Gnomad AMR exome AF: 0.00

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: 0.0000354

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000390 AC: 57 AN: 1461802 Hom.: 0 Cov.: 32 AF XY: 0.0000468 AC XY: 34 AN XY: 727200

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: 0.0000504

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 09, 2023

The c.1362A>C (p.K454N) alteration is located in exon 8 (coding exon 8) of the RPAP2 gene. This alteration results from a A to C substitution at nucleotide position 1362, causing the lysine (K) at amino acid position 454 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.065	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
PrimateAI	Benign	0.43	T
Sift4G	Uncertain	0.016	D
Polyphen		0.015	B
Vest4		0.28
MutPred		0.23		Gain of ubiquitination at K453 (P = 0.0239);
MVP		0.52
MPC		0.42
ClinPred		0.82	D
GERP RS		0.51
Varity_R		0.15
gMVP		0.15

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: rs752016109; hg19: chr1-92789839; COSMIC: COSV72509520; COSMIC: COSV72509520;