Genetic Variant NR1H2:c.182-80T>C (chr19-50378069-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_007121.7(NR1H2):c.182-80T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.336 in 1,482,382 control chromosomes in the GnomAD database, including 85,765 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.36 ( 10410 hom., cov: 32)

Exomes 𝑓: 0.33 ( 75355 hom. )

Consequence

NR1H2
NM_007121.7 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.505

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 made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 19-50378069-T-C is Benign according to our data. Variant chr19-50378069-T-C is described in ClinVar as [Benign]. Clinvar id is 1277347.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.436 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR1H2	NM_007121.7 link	c.182-80T>C		intron_variant	Intron 4 of 9	ENST00000253727.10	NP_009052.4	P55055-1F1D8P7
NR1H2	NM_001256647.3 link	c.181+199T>C		intron_variant	Intron 4 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.182-80T>C		intron_variant	Intron 4 of 9	1	NM_007121.7	ENSP00000253727.4		P55055-1

Frequencies

GnomAD3 genomes

AF:

0.363

AC:

55159

AN:

151998

Hom.:

10392

Cov.:

show subpopulations

Gnomad AFR

AF:

0.441

Gnomad AMI

AF:

0.378

Gnomad AMR

AF:

0.409

Gnomad ASJ

AF:

0.390

Gnomad EAS

AF:

0.158

Gnomad SAS

AF:

0.384

Gnomad FIN

AF:

0.295

Gnomad MID

AF:

0.364

Gnomad NFE

AF:

0.329

Gnomad OTH

AF:

0.350

GnomAD4 exome

AF:

0.333

AC:

442821

AN:

1330266

Hom.:

75355

Cov.:

AF XY:

0.334

AC XY:

218580

AN XY:

653904

show subpopulations

Gnomad4 AFR exome

AF:

0.445

Gnomad4 AMR exome

AF:

0.450

Gnomad4 ASJ exome

AF:

0.387

Gnomad4 EAS exome

AF:

0.166

Gnomad4 SAS exome

AF:

0.383

Gnomad4 FIN exome

AF:

0.302

Gnomad4 NFE exome

AF:

0.329

Gnomad4 OTH exome

AF:

0.332

GnomAD4 genome

AF:

0.363

AC:

55232

AN:

152116

Hom.:

10410

Cov.:

AF XY:

0.362

AC XY:

26895

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.441

Gnomad4 AMR

AF:

0.409

Gnomad4 ASJ

AF:

0.390

Gnomad4 EAS

AF:

0.159

Gnomad4 SAS

AF:

0.385

Gnomad4 FIN

AF:

0.295

Gnomad4 NFE

AF:

0.329

Gnomad4 OTH

AF:

0.346

Alfa

AF:

0.233

Hom.:

566

Bravo

AF:

0.370

Asia WGS

AF:

0.291

AC:

1011

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 24, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 20939869) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.44

DANN

Benign

0.41

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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