1-178821646-T-C
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_152663.5(RALGPS2):c.422T>C(p.Met141Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,478 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
RALGPS2
NM_152663.5 missense
NM_152663.5 missense
Scores
6
8
4
Clinical Significance
Conservation
PhyloP100: 7.58
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.804
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RALGPS2 | NM_152663.5 | c.422T>C | p.Met141Thr | missense_variant | 7/20 | ENST00000367635.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RALGPS2 | ENST00000367635.8 | c.422T>C | p.Met141Thr | missense_variant | 7/20 | 1 | NM_152663.5 | P3 | |
RALGPS2 | ENST00000367634.7 | c.422T>C | p.Met141Thr | missense_variant | 7/19 | 2 | A1 | ||
RALGPS2 | ENST00000324778.5 | c.317T>C | p.Met106Thr | missense_variant | 6/10 | 5 | |||
RALGPS2 | ENST00000495034.5 | n.760T>C | non_coding_transcript_exon_variant | 7/10 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461478Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2AN XY: 727008
GnomAD4 exome
AF:
AC:
4
AN:
1461478
Hom.:
Cov.:
30
AF XY:
AC XY:
2
AN XY:
727008
Gnomad4 AFR exome
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Gnomad4 EAS exome
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Gnomad4 SAS exome
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Gnomad4 FIN exome
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
Bravo
AF:
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 | Feb 28, 2024 | The c.422T>C (p.M141T) alteration is located in exon 7 (coding exon 6) of the RALGPS2 gene. This alteration results from a T to C substitution at nucleotide position 422, causing the methionine (M) at amino acid position 141 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
Cadd
Pathogenic
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Benign
T
MutationAssessor
Benign
L;L;.
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;D
REVEL
Uncertain
Sift
Uncertain
D;D;D
Sift4G
Uncertain
D;T;D
Polyphen
0.97
.;D;.
Vest4
MutPred
Loss of stability (P = 0.0502);Loss of stability (P = 0.0502);.;
MVP
MPC
1.4
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at