1-178776799-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152663.5(RALGPS2):c.35A>T(p.Asn12Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: RALGPS2 NM_152663.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.19

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0809319).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RALGPS2	NM_152663.5	c.35A>T	p.Asn12Ile	missense_variant	2/20	ENST00000367635.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RALGPS2	ENST00000367635.8	c.35A>T	p.Asn12Ile	missense_variant	2/20	1	NM_152663.5	P3
RALGPS2	ENST00000367634.7	c.35A>T	p.Asn12Ile	missense_variant	2/19	2		A1
RALGPS2	ENST00000324778.5	c.35A>T	p.Asn12Ile	missense_variant	2/10	5
RALGPS2	ENST00000495034.5	n.373A>T		non_coding_transcript_exon_variant	2/10	2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 30

Bravo AF: 0.00000756

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

Jan 03, 2024

The c.35A>T (p.N12I) alteration is located in exon 2 (coding exon 1) of the RALGPS2 gene. This alteration results from a A to T substitution at nucleotide position 35, causing the asparagine (N) at amino acid position 12 to be replaced by an isoleucine (I). 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	0.086
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	13
Dann	Benign	0.97
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.75	T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.081	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.14	N;N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.3	N;N;N
REVEL	Benign	0.033
Sift	Benign	0.099	T;T;D
Sift4G	Benign	0.23	T;T;T
Polyphen		0.0050	.;B;.
Vest4		0.76
MutPred		0.38		Gain of sheet (P = 0.0149);Gain of sheet (P = 0.0149);Gain of sheet (P = 0.0149);
MVP		0.082
MPC		0.58
ClinPred		0.11	T
GERP RS		1.4
Varity_R		0.083
gMVP		0.40

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: rs745958556; hg19: chr1-178745934;