X-47089838-C-G

Variant names:

• chrX-47089838-C-G
• rs1556386592
• NM_152869.4:c.409C>G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_152869.4(RGN):​c.409C>G​(p.Leu137Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,097,430 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 19)
  • Exomes 𝑓: 0.0000055 (0 hom. 3 hem.)
• Consequence: RGN NM_152869.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.97

Genes affected

RGN (HGNC:9989): (regucalcin) The protein encoded by this gene is a highly conserved, calcium-binding protein, that is preferentially expressed in the liver and kidney. It may have an important role in calcium homeostasis. Studies in rat indicate that this protein may also play a role in aging, as it shows age-associated down-regulation. This gene is part of a gene cluster on chromosome Xp11.3-Xp11.23. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.38123193).
• BS2: High Hemizygotes in GnomAdExome4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RGN	NM_152869.4	c.409C>G	p.Leu137Val	missense_variant	Exon 5 of 8	ENST00000397180.6	NP_690608.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RGN	ENST00000397180.6	c.409C>G	p.Leu137Val	missense_variant	Exon 5 of 8	5	NM_152869.4	ENSP00000380365.1

Frequencies

GnomAD3 genomes Cov.: 19

GnomAD4 exome AF: 0.00000547 AC: 6 AN: 1097430 Hom.: 0 Cov.: 29 AF XY: 0.00000827 AC XY: 3 AN XY: 362818

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: 0.0000370

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000475

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 19

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 14, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.409C>G (p.L137V) alteration is located in exon 5 (coding exon 3) of the RGN gene. This alteration results from a C to G substitution at nucleotide position 409, causing the leucine (L) at amino acid position 137 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	0.19
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.33	T;T;T
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.85	T;.;.
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.38	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;L;L
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.9	N;N;N
REVEL	Benign	0.14
Sift	Benign	0.075	T;T;T
Sift4G	Benign	0.11	T;T;T
Polyphen		0.33	B;B;B
Vest4		0.34
MutPred		0.68		Loss of stability (P = 0.0137);Loss of stability (P = 0.0137);Loss of stability (P = 0.0137);
MVP		0.51
MPC		0.027
ClinPred		0.81	D
GERP RS		5.5
Varity_R		0.64
gMVP		0.44

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: rs1556386592; hg19: chrX-46949237; COSMIC: COSV60275773; COSMIC: COSV60275773;