X-130412484-C-T

Variant names:

• chrX-130412484-C-T
• rs2034519148
• NM_016024.4:c.605C>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_016024.4(RBMX2):​c.605C>T​(p.Pro202Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000273 in 1,098,049 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P202S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 20)
  • Exomes 𝑓: 0.0000027 (0 hom. 0 hem.)
• Consequence: RBMX2 NM_016024.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0260

Genes affected

RBMX2 (HGNC:24282): (RNA binding motif protein X-linked 2) Enables RNA binding activity. Involved in mRNA splicing, via spliceosome. Located in nucleus. Part of U2-type precatalytic spliceosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.064299166).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBMX2	NM_016024.4	c.605C>T	p.Pro202Leu	missense_variant	Exon 6 of 6	ENST00000305536.11	NP_057108.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBMX2	ENST00000305536.11	c.605C>T	p.Pro202Leu	missense_variant	Exon 6 of 6	1	NM_016024.4	ENSP00000339090.4
RBMX2	ENST00000487274.1	n.*89C>T		downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD4 exome AF: 0.00000273 AC: 3 AN: 1098049 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 363511

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000356

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 20

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.605C>T (p.P202L) alteration is located in exon 6 (coding exon 6) of the RBMX2 gene. This alteration results from a C to T substitution at nucleotide position 605, causing the proline (P) at amino acid position 202 to be replaced by a leucine (L). 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	0.075
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.95
CADD	Benign	3.8
DANN	Benign	0.41
DEOGEN2	Benign	0.13	T;.
FATHMM_MKL	Benign	0.0079	N
LIST_S2	Benign	0.69	T;T
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.064	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L;.
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.6	N;.
REVEL	Benign	0.069
Sift	Benign	0.095	T;.
Sift4G	Benign	0.79	T;.
Polyphen		0.0060	B;.
Vest4		0.043
MutPred		0.28		Gain of catalytic residue at P202 (P = 0.0203);Gain of catalytic residue at P202 (P = 0.0203);
MVP		0.11
MPC		0.37
ClinPred		0.039	T
GERP RS		0.50
Varity_R		0.046
gMVP		0.068

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: rs2034519148; hg19: chrX-129546458;