Genetic Variant RGN:p.His142Gln (chrX-47089855-C-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_152869.4(RGN):c.426C>A(p.His142Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000879 in 1,205,453 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 52 hemizygotes 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 (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., 1 hem., cov: 20)

Exomes 𝑓: 0.000092 ( 0 hom. 51 hem. )

Consequence

RGN
NM_152869.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.63

Variant links:

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]

RGN links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014323086).

BS2

High Hemizygotes in GnomAdExome4 at 51 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RGN	NM_152869.4 link	c.426C>A	p.His142Gln	missense_variant	Exon 5 of 8	ENST00000397180.6	NP_690608.1	Q15493-1V9HWF8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RGN	ENST00000397180.6 link	c.426C>A	p.His142Gln	missense_variant	Exon 5 of 8	5	NM_152869.4	ENSP00000380365.1		Q15493-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

108642

Hom.:

Cov.:

AF XY:

0.0000322

AC XY:

AN XY:

31010

show subpopulations

Gnomad AFR

AF:

0.0000671

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000390

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000380

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000120

AC:

AN:

182688

Hom.:

AF XY:

0.000253

AC XY:

AN XY:

67184

show subpopulations

Gnomad AFR exome

AF:

0.0000762

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000633

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000110

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000921

AC:

101

AN:

1096811

Hom.:

Cov.:

AF XY:

0.000141

AC XY:

AN XY:

362213

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000284

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000518

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000809

Gnomad4 OTH exome

AF:

0.0000869

GnomAD4 genome

AF:

0.0000460

AC:

AN:

108642

Hom.:

Cov.:

AF XY:

0.0000322

AC XY:

AN XY:

31010

show subpopulations

Gnomad4 AFR

AF:

0.0000671

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000390

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000380

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.000148

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000298

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 23, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.426C>A (p.H142Q) alteration is located in exon 5 (coding exon 3) of the RGN gene. This alteration results from a C to A substitution at nucleotide position 426, causing the histidine (H) at amino acid position 142 to be replaced by a glutamine (Q). 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

0.094

BayesDel_addAF

Benign

-0.83

BayesDel_noAF

Benign

-1.1

CADD

Benign

0.0010

DANN

Benign

0.78

DEOGEN2

Benign

0.11

T;T;T

FATHMM_MKL

Benign

0.077

LIST_S2

Benign

0.16

T;.;.

M_CAP

Benign

0.0034

MetaRNN

Benign

0.014

T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.88

N;N;N

PrimateAI

Benign

0.34

PROVEAN

Benign

0.78

N;N;N

REVEL

Benign

0.048

Sift

Benign

0.090

T;T;T

Sift4G

Benign

0.47

T;T;T

Polyphen

0.0

B;B;B

Vest4

0.085

MutPred

0.38

Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);

MVP

0.29

MPC

0.017

ClinPred

0.035

GERP RS

-11

Varity_R

0.21

gMVP

0.26

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over