2-112388201-T-C

Variant names:

• chr2-112388201-T-C
• NM_001164463.1:c.4744A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001164463.1(RGPD8):​c.4744A>G​(p.Ser1582Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 15)
  • Exomes 𝑓: 0.0000046 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RGPD8 NM_001164463.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.673
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.053955197).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001164463.1. 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
	RGPD8	NM_001164463.1	MANE Select	c.4744A>G	p.Ser1582Gly	missense	Exon 20 of 23	NP_001157935.1	O14715

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RGPD8	ENST00000302558.8	TSL:1 MANE Select	c.4744A>G	p.Ser1582Gly	missense	Exon 20 of 23	ENSP00000306637.3	O14715
	RGPD8	ENST00000409750.5	TSL:1	c.4324A>G	p.Ser1442Gly	missense	Exon 19 of 22	ENSP00000386511.1	J3KQ37
	RGPD8	ENST00000929966.1		c.2707A>G	p.Ser903Gly	missense	Exon 7 of 10	ENSP00000600025.1

Frequencies

GnomAD3 genomes Cov.: 15

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000461 AC: 6 AN: 1301828 Hom.: 0 Cov.: 23 AF XY: 0.00000614 AC XY: 4 AN XY: 650958

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 29620

American (AMR) AF: 0.00 AC: 0 AN: 38210

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23556

East Asian (EAS) AF: 0.0000260 AC: 1 AN: 38402

South Asian (SAS) AF: 0.0000389 AC: 3 AN: 77144

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50966

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3688

European-Non Finnish (NFE) AF: 0.00000203 AC: 2 AN: 985444

Other (OTH) AF: 0.00 AC: 0 AN: 54798

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000000852607), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 15

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	10
DANN	Benign	0.95
DEOGEN2	Benign	0.0062	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.054	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.67
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.029
Sift	Benign	0.40	T
Sift4G	Benign	0.44	T
Polyphen		0.0	B
Vest4		0.056
MutPred		0.11		Loss of phosphorylation at S1582 (P = 0.0211)
MVP		0.014
ClinPred		0.052	T
GERP RS		-0.38
Varity_R		0.055
gMVP		0.0097
Mutation Taster		=80/20	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

hg19: chr2-113145778;