2-112388555-T-C

Position:

• chr2-112388555-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000302558.8(RGPD8):​c.4390A>G​(p.Lys1464Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 12)
• Consequence: RGPD8 ENST00000302558.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.92

Genes affected

RGPD8 (HGNC:9849): (RANBP2 like and GRIP domain containing 8) Predicted to contribute to GTPase activator activity. Predicted to be involved in NLS-bearing protein import into nucleus. Predicted to be part of nuclear pore. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3890321).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RGPD8	NM_001164463.1	c.4390A>G	p.Lys1464Glu	missense_variant	20/23	ENST00000302558.8	NP_001157935.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RGPD8	ENST00000302558.8	c.4390A>G	p.Lys1464Glu	missense_variant	20/23	1	NM_001164463.1	ENSP00000306637.3
RGPD8	ENST00000409750.5	c.3970A>G	p.Lys1324Glu	missense_variant	19/22	1		ENSP00000386511.1

Frequencies

GnomAD3 genomes Cov.: 12

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 12

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

Oct 20, 2023

The c.4390A>G (p.K1464E) alteration is located in exon 20 (coding exon 20) of the RGPD8 gene. This alteration results from a A to G substitution at nucleotide position 4390, causing the lysine (K) at amino acid position 1464 to be replaced by a glutamic acid (E). 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	Uncertain	0.46
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T;T
Eigen	Uncertain	0.30
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.39	T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.7	M;.
MutationTaster	Benign	0.95	N;N
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-2.3	N;N
REVEL	Benign	0.21
Sift	Uncertain	0.014	D;D
Sift4G	Uncertain	0.016	D;D
Polyphen		0.99	D;.
Vest4		0.54
MutPred		0.45		Loss of ubiquitination at K1464 (P = 0.021);.;
MVP		0.040
ClinPred		0.89	D
GERP RS		2.3
Varity_R		0.30
gMVP		0.026

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: rs1351929731; hg19: chr2-113146132;