Genetic Variant NR1H2:c.748-87C>T (chr19-50378915-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 NM_007121.7(NR1H2):c.748-87C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.323 in 1,545,210 control chromosomes in the GnomAD database, including 82,696 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 0.29 ( 6944 hom., cov: 32)

Exomes 𝑓: 0.33 ( 75752 hom. )

Consequence

NR1H2
NM_007121.7 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.194

Publications

11 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=-0.88).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.371 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR1H2	NM_007121.7 link	c.748-87C>T		intron_variant	Intron 6 of 9	ENST00000253727.10	NP_009052.4	P55055-1F1D8P7
NR1H2	NM_001256647.3 link	c.457-87C>T		intron_variant	Intron 5 of 8		NP_001243576.2	P55055-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR1H2	ENST00000253727.10 link	c.748-87C>T		intron_variant	Intron 6 of 9	1	NM_007121.7	ENSP00000253727.4		P55055-1

Frequencies

GnomAD3 genomes

AF:

0.295

AC:

44743

AN:

151852

Hom.:

6942

Cov.:

show subpopulations

Gnomad AFR

AF:

0.207

Gnomad AMI

AF:

0.378

Gnomad AMR

AF:

0.379

Gnomad ASJ

AF:

0.386

Gnomad EAS

AF:

0.160

Gnomad SAS

AF:

0.365

Gnomad FIN

AF:

0.295

Gnomad MID

AF:

0.348

Gnomad NFE

AF:

0.328

Gnomad OTH

AF:

0.302

GnomAD4 exome

AF:

0.326

AC:

454267

AN:

1393240

Hom.:

75752

Cov.:

AF XY:

0.328

AC XY:

224923

AN XY:

686190

show subpopulations

African (AFR)

AF:

0.203

AC:

6467

AN:

31854

American (AMR)

AF:

0.438

AC:

16741

AN:

38214

Ashkenazi Jewish (ASJ)

AF:

0.381

AC:

8284

AN:

21726

East Asian (EAS)

AF:

0.169

AC:

6629

AN:

39168

South Asian (SAS)

AF:

0.367

AC:

27789

AN:

75790

European-Finnish (FIN)

AF:

0.305

AC:

14776

AN:

48478

Middle Eastern (MID)

AF:

0.375

AC:

2009

AN:

5364

European-Non Finnish (NFE)

AF:

0.329

AC:

353556

AN:

1075274

Other (OTH)

AF:

0.314

AC:

18016

AN:

57372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

16848

33696

50545

67393

84241

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11704

23408

35112

46816

58520

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.295

AC:

44764

AN:

151970

Hom.:

6944

Cov.:

AF XY:

0.295

AC XY:

21917

AN XY:

74292

show subpopulations

African (AFR)

AF:

0.206

AC:

8560

AN:

41496

American (AMR)

AF:

0.379

AC:

5786

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.386

AC:

1338

AN:

3466

East Asian (EAS)

AF:

0.161

AC:

834

AN:

5178

South Asian (SAS)

AF:

0.365

AC:

1757

AN:

4810

European-Finnish (FIN)

AF:

0.295

AC:

3105

AN:

10540

Middle Eastern (MID)

AF:

0.350

AC:

103

AN:

294

European-Non Finnish (NFE)

AF:

0.329

AC:

22308

AN:

67908

Other (OTH)

AF:

0.298

AC:

629

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1621

3242

4863

6484

8105

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

464

928

1392

1856

2320

<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:

0.311

Hom.:

952

Bravo

AF:

0.293

Asia WGS

AF:

0.251

AC:

872

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

2.0

(source)

DANN

Benign

0.68

PhyloP100

-0.19

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over