rs144538512

Variant names:

• chr20-37184354-C-T
• rs144538512
• NM_002951.5:c.188C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_002951.5(RPN2):​c.188C>T​(p.Ala63Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000248 in 1,614,198 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: RPN2 NM_002951.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.683
• Publications: 2 publications found

Genes affected

RPN2 (HGNC:10382): (ribophorin II) This gene encodes a type I integral membrane protein found only in the rough endoplasmic reticulum. The encoded protein is part of an N-oligosaccharyl transferase complex that links high mannose oligosaccharides to asparagine residues found in the Asn-X-Ser/Thr consensus motif of nascent polypeptide chains. This protein is similar in sequence to the yeast oligosaccharyl transferase subunit SWP1. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014599979).
• BP6: Variant 20-37184354-C-T is Benign according to our data. Variant chr20-37184354-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 572778.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002951.5. 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
	RPN2	NM_002951.5	MANE Select	c.188C>T	p.Ala63Val	missense	Exon 2 of 17	NP_002942.2
	RPN2	NM_001324301.2		c.188C>T	p.Ala63Val	missense	Exon 2 of 19	NP_001311230.1
	RPN2	NM_001324304.2		c.188C>T	p.Ala63Val	missense	Exon 2 of 18	NP_001311233.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPN2	ENST00000237530.11	TSL:1 MANE Select	c.188C>T	p.Ala63Val	missense	Exon 2 of 17	ENSP00000237530.6	P04844-1
	RPN2	ENST00000705448.1		c.188C>T	p.Ala63Val	missense	Exon 2 of 18	ENSP00000516126.1	A0A994J5J1
	RPN2	ENST00000892636.1		c.188C>T	p.Ala63Val	missense	Exon 2 of 18	ENSP00000562695.1

Frequencies

GnomAD3 genomes AF: 0.000434 AC: 66 AN: 152222 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000485 AC: 122 AN: 251468 AF XY: 0.000500

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00121

Gnomad ASJ exome AF: 0.00268

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000378

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000229 AC: 335 AN: 1461858 Hom.: 0 Cov.: 32 AF XY: 0.000243 AC XY: 177 AN XY: 727228

African (AFR) AF: 0.000269 AC: 9 AN: 33480

American (AMR) AF: 0.00116 AC: 52 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00199 AC: 52 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.00485 AC: 28 AN: 5768

European-Non Finnish (NFE) AF: 0.000136 AC: 151 AN: 1111980

Other (OTH) AF: 0.000613 AC: 37 AN: 60394

GnomAD4 genome AF: 0.000427 AC: 65 AN: 152340 Hom.: 0 Cov.: 32 AF XY: 0.000430 AC XY: 32 AN XY: 74492

African (AFR) AF: 0.0000962 AC: 4 AN: 41586

American (AMR) AF: 0.00248 AC: 38 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000415 Hom.: 0

Bravo AF: 0.000465

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000354 AC: 43

EpiCase AF: 0.000164

EpiControl AF: 0.000474

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Congenital disorder of glycosylation (1)
-	-	1	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	17
DANN	Benign	0.90
DEOGEN2	Benign	0.063	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.68
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.92	N
REVEL	Benign	0.024
Sift	Benign	0.27	T
Sift4G	Benign	0.56	T
Polyphen		0.0	B
Vest4		0.24
MVP		0.39
MPC		0.16
ClinPred		0.018	T
GERP RS		1.7
Varity_R		0.032
gMVP		0.33
Mutation Taster		=93/7	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: rs144538512; hg19: chr20-35812757;