Genetic Variant NM_152869.4:c.426C>G (chrX-47089855-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_152869.4(RGN):c.426C>G(p.His142Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000184 in 108,642 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 1 hem., cov: 20)

Consequence

RGN
NM_152869.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.63

Publications

0 publications found

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:

ENSG00000307069 (HGNC:):

ENSG00000307069 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.030187607).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152869.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RGN	NM_152869.4	MANE Select	c.426C>G	p.His142Gln	missense	Exon 5 of 8	NP_690608.1	Q15493-1
RGN	NM_004683.6		c.426C>G	p.His142Gln	missense	Exon 4 of 7	NP_004674.1	Q15493-1
RGN	NM_001282848.2		c.267C>G	p.His89Gln	missense	Exon 5 of 8	NP_001269777.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RGN	ENST00000397180.6	TSL:5 MANE Select	c.426C>G	p.His142Gln	missense	Exon 5 of 8	ENSP00000380365.1	Q15493-1
RGN	ENST00000336169.3	TSL:1	c.426C>G	p.His142Gln	missense	Exon 4 of 7	ENSP00000338400.3	Q15493-1
RGN	ENST00000352078.8	TSL:1	c.426C>G	p.His142Gln	missense	Exon 4 of 7	ENSP00000253303.4	Q15493-1

Frequencies

GnomAD3 genomes

AF:

0.0000184

AC:

AN:

108642

Hom.:

Cov.:

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.0000184

AC:

AN:

108642

Hom.:

Cov.:

AF XY:

0.0000322

AC XY:

AN XY:

31010

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000671

AC:

AN:

29808

American (AMR)

AF:

0.00

AC:

AN:

9748

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2628

East Asian (EAS)

AF:

0.00

AC:

AN:

3474

South Asian (SAS)

AF:

0.00

AC:

AN:

2566

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5442

Middle Eastern (MID)

AF:

0.00

AC:

AN:

232

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

52629

Other (OTH)

AF:

0.00

AC:

AN:

1441

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-1.1

CADD

Benign

0.0020

(source)

DANN

Benign

0.66

DEOGEN2

Benign

0.11

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.16

M_CAP

Benign

0.0031

MetaRNN

Benign

0.030

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.88

PhyloP100

-1.6

PrimateAI

Benign

0.34

PROVEAN

Benign

0.78

REVEL

Benign

0.048

Sift

Benign

0.090

Sift4G

Benign

0.47

Polyphen

0.0

Vest4

0.085

MutPred

0.38

Loss of sheet (P = 0.0817)

MVP

0.29

MPC

0.017

ClinPred

0.10

GERP RS

-11

Varity_R

0.21

gMVP

0.26

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over