Genetic Variant NR1H2:c.-127-424C>T (chr19-50376295-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000600355.5(NR1H2):c.-127-424C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.059 in 152,300 control chromosomes in the GnomAD database, including 363 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.059 ( 363 hom., cov: 32)

Exomes 𝑓: 0.083 ( 0 hom. )

Consequence

NR1H2
ENST00000600355.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.21

Publications

4 publications found

Variant links:

Genes affected

NR1H2 (HGNC:7965): (nuclear receptor subfamily 1 group H member 2) The liver X receptors, LXRA (NR1H3; MIM 602423) and LXRB, form a subfamily of the nuclear receptor superfamily and are key regulators of macrophage function, controlling transcriptional programs involved in lipid homeostasis and inflammation. The inducible LXRA is highly expressed in liver, adrenal gland, intestine, adipose tissue, macrophages, lung, and kidney, whereas LXRB is ubiquitously expressed. Ligand-activated LXRs form obligate heterodimers with retinoid X receptors (RXRs; see MIM 180245) and regulate expression of target genes containing LXR response elements (summary by Korf et al., 2009 [PubMed 19436111]).[supplied by OMIM, Jan 2010]

NR1H2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0814 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000600355.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR1H2	NM_007121.7	MANE Select	c.-409C>T		upstream_gene	N/A	NP_009052.4	P55055-1
	NR1H2	NM_001256647.3		c.-409C>T		upstream_gene	N/A	NP_001243576.2	P55055-2

Ensembl Transcripts

Gene	Transcript	HGVSc	Effect	Exon Rank	Protein	UniProt
NR1H2	ENST00000652203.1	c.-127-424C>T	intron	N/A	ENSP00000499121.1	P55055-1
NR1H2	ENST00000939061.1	c.-127-424C>T	intron	N/A	ENSP00000609120.1
NR1H2	ENST00000939062.1	c.-127-424C>T	intron	N/A	ENSP00000609121.1

Frequencies

GnomAD3 genomes

AF:

0.0590

AC:

8977

AN:

152158

Hom.:

362

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0184

Gnomad AMI

AF:

0.182

Gnomad AMR

AF:

0.0567

Gnomad ASJ

AF:

0.119

Gnomad EAS

AF:

0.00830

Gnomad SAS

AF:

0.0884

Gnomad FIN

AF:

0.0694

Gnomad MID

AF:

0.0759

Gnomad NFE

AF:

0.0790

Gnomad OTH

AF:

0.0774

GnomAD4 exome

AF:

0.0833

AC:

AN:

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AF:

0.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.125

AC:

AN:

Other (OTH)

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0590

AC:

8981

AN:

152276

Hom.:

363

Cov.:

AF XY:

0.0593

AC XY:

4416

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.0184

AC:

765

AN:

41570

American (AMR)

AF:

0.0566

AC:

866

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.119

AC:

414

AN:

3472

East Asian (EAS)

AF:

0.00812

AC:

AN:

5170

South Asian (SAS)

AF:

0.0883

AC:

426

AN:

4826

European-Finnish (FIN)

AF:

0.0694

AC:

736

AN:

10600

Middle Eastern (MID)

AF:

0.0782

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0790

AC:

5375

AN:

68014

Other (OTH)

AF:

0.0795

AC:

168

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

439

877

1316

1754

2193

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

216

324

432

540

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0664

Hom.:

805

Bravo

AF:

0.0557

Asia WGS

AF:

0.0440

AC:

152

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

6.7

(source)

DANN

Benign

0.78

PhyloP100

1.2

PromoterAI

-0.00050

Neutral

(source)

Mutation Taster

=300/0

polymorphism (auto)

(source)

Splicing

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over