Variant 1-178785606-A-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_152663.5(RALGPS2):c.212A>T(p.Asp71Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000021 in 1,429,872 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

RALGPS2
NM_152663.5 missense, splice_region

Scores

Splicing: ADA: 0.9988

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.23

Variant links:

Genes affected

RALGPS2 (HGNC:30279): (Ral GEF with PH domain and SH3 binding motif 2) Predicted to enable guanyl-nucleotide exchange factor activity. Predicted to be involved in regulation of Ral protein signal transduction; regulation of catalytic activity; and small GTPase mediated signal transduction. Predicted to be located in cytoplasm and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

RALGPS2 links:

RALGPS2 (HGNC:):

RALGPS2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RALGPS2	NM_152663.5 linkuse as main transcript	c.212A>T	p.Asp71Val	missense_variant, splice_region_variant	4/20	ENST00000367635.8	NP_689876.2	Q86X27-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
RALGPS2	ENST00000367635.8 linkuse as main transcript	c.212A>T	p.Asp71Val	missense_variant, splice_region_variant	4/20	1	NM_152663.5	ENSP00000356607.3	Q86X27-1
RALGPS2	ENST00000367634.7 linkuse as main transcript	c.212A>T	p.Asp71Val	missense_variant, splice_region_variant	4/19	2		ENSP00000356606.2	Q86X27-3
RALGPS2	ENST00000324778.5 linkuse as main transcript	c.107A>T	p.Asp36Val	missense_variant, splice_region_variant	3/10	5		ENSP00000313613.5	A0A0A0MR31
RALGPS2	ENST00000495034.5 linkuse as main transcript	n.550A>T		splice_region_variant, non_coding_transcript_exon_variant	4/10	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000872

AC:

AN:

229274

Hom.:

AF XY:

0.0000161

AC XY:

AN XY:

124552

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000380

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000939

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000210

AC:

AN:

1429872

Hom.:

Cov.:

AF XY:

0.00000281

AC XY:

AN XY:

710720

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000374

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 12, 2023

The c.212A>T (p.D71V) alteration is located in exon 4 (coding exon 3) of the RALGPS2 gene. This alteration results from a A to T substitution at nucleotide position 212, causing the aspartic acid (D) at amino acid position 71 to be replaced by a valine (V). 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

0.32

BayesDel_addAF

Benign

-0.060

BayesDel_noAF

Benign

-0.21

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.16

.;T;T

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Benign

0.028

MetaRNN

Uncertain

0.57

D;D;D

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

L;L;.

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-5.3

D;D;D

REVEL

Uncertain

0.37

Sift

Uncertain

0.0010

D;D;D

Sift4G

Uncertain

0.0020

D;D;D

Polyphen

0.42

.;B;.

Vest4

0.58

MutPred

0.54

Loss of catalytic residue at D71 (P = 0.0939);Loss of catalytic residue at D71 (P = 0.0939);.;

MVP

0.20

MPC

0.93

ClinPred

0.97

GERP RS

5.3

Varity_R

0.66

gMVP

0.50

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

0.060

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over