2-112388101-C-T

Variant names:

• chr2-112388101-C-T
• rs1166499166
• NM_001164463.1:c.4844G>A

Variant summary

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

The NM_001164463.1(RGPD8):​c.4844G>A​(p.Ser1615Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000025 (0 hom., cov: 15)
  • Exomes 𝑓: 0.000060 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RGPD8 NM_001164463.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.99
• 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=0.054511935).

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.4844G>A	p.Ser1615Asn	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.4844G>A	p.Ser1615Asn	missense	Exon 20 of 23	ENSP00000306637.3	O14715
	RGPD8	ENST00000409750.5	TSL:1	c.4424G>A	p.Ser1475Asn	missense	Exon 19 of 22	ENSP00000386511.1	J3KQ37
	RGPD8	ENST00000929966.1		c.2807G>A	p.Ser936Asn	missense	Exon 7 of 10	ENSP00000600025.1

Frequencies

GnomAD3 genomes AF: 0.0000252 AC: 3 AN: 119216 Hom.: 0 Cov.: 15

Gnomad AFR AF: 0.0000319

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000357

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000602 AC: 61 AN: 1013504 Hom.: 0 Cov.: 14 AF XY: 0.0000608 AC XY: 31 AN XY: 509458

⚠️ 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: 23340

American (AMR) AF: 0.00 AC: 0 AN: 24128

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18414

East Asian (EAS) AF: 0.00 AC: 0 AN: 36366

South Asian (SAS) AF: 0.00 AC: 0 AN: 61414

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40636

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3064

European-Non Finnish (NFE) AF: 0.0000775 AC: 59 AN: 761182

Other (OTH) AF: 0.0000445 AC: 2 AN: 44960

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000252 AC: 3 AN: 119216 Hom.: 0 Cov.: 15 AF XY: 0.0000176 AC XY: 1 AN XY: 56736

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

African (AFR) AF: 0.0000319 AC: 1 AN: 31324

American (AMR) AF: 0.00 AC: 0 AN: 11330

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2828

East Asian (EAS) AF: 0.00 AC: 0 AN: 4602

South Asian (SAS) AF: 0.00 AC: 0 AN: 3070

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7570

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 280

European-Non Finnish (NFE) AF: 0.0000357 AC: 2 AN: 56068

Other (OTH) AF: 0.00 AC: 0 AN: 1490

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000000178044), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

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	0.084
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	18
DANN	Benign	0.84
DEOGEN2	Benign	0.0025	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.055	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.14	N
PhyloP100		2.0
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.78	N
REVEL	Benign	0.073
Sift	Benign	0.20	T
Sift4G	Benign	0.15	T
Polyphen		0.0010	B
Vest4		0.051
MutPred		0.24		Gain of relative solvent accessibility (P = 0.0082)
MVP		0.014
ClinPred		0.027	T
GERP RS		1.4
Varity_R		0.13
gMVP		0.017
Mutation Taster		=97/3	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: rs1166499166; hg19: chr2-113145678;