1-178821646-T-C

Variant names:

• chr1-178821646-T-C
• rs1655511948
• NM_152663.5:c.422T>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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]

ACMG classification

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 rank	MANE	Protein	UniProt
RALGPS2	NM_152663.5	c.422T>C	p.Met141Thr	missense_variant	Exon 7 of 20	ENST00000367635.8	NP_689876.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RALGPS2	ENST00000367635.8	c.422T>C	p.Met141Thr	missense_variant	Exon 7 of 20	1	NM_152663.5	ENSP00000356607.3
RALGPS2	ENST00000367634.7	c.422T>C	p.Met141Thr	missense_variant	Exon 7 of 19	2		ENSP00000356606.2
RALGPS2	ENST00000324778.5	c.317T>C	p.Met106Thr	missense_variant	Exon 6 of 10	5		ENSP00000313613.5
RALGPS2	ENST00000495034.5	n.760T>C		non_coding_transcript_exon_variant	Exon 7 of 10	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461478 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727008

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	.;T;T
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Benign	0.028	D
MetaRNN	Pathogenic	0.80	D;D;D
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.8	L;L;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.4	D;D;D
REVEL	Uncertain	0.43
Sift	Uncertain	0.011	D;D;D
Sift4G	Uncertain	0.049	D;T;D
Polyphen		0.97	.;D;.
Vest4		0.86
MutPred		0.74		Loss of stability (P = 0.0502);Loss of stability (P = 0.0502);.;
MVP		0.39
MPC		1.4
ClinPred		0.98	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.61
gMVP		0.79

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: rs1655511948; hg19: chr1-178790781; COSMIC: COSV61338322;