rs2248949

Positions:

• chr19-50378912-A-G
• chr19-50378912-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_007121.7(NR1H2):​c.748-90A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.598 in 1,544,118 control chromosomes in the GnomAD database, including 280,683 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 0.65 (32775 hom., cov: 32)
  • Exomes 𝑓: 0.59 (247908 hom.)
• Consequence: NR1H2 NM_007121.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0990

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.847 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NR1H2	NM_007121.7	c.748-90A>G		intron_variant		ENST00000253727.10	NP_009052.4
NR1H2	NM_001256647.3	c.457-90A>G		intron_variant			NP_001243576.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NR1H2	ENST00000253727.10	c.748-90A>G		intron_variant		1	NM_007121.7	ENSP00000253727	P1

Frequencies

GnomAD3 genomes AF: 0.649 AC: 98497 AN: 151776 Hom.: 32705 Cov.: 32

Gnomad AFR AF: 0.763

Gnomad AMI AF: 0.635

Gnomad AMR AF: 0.651

Gnomad ASJ AF: 0.738

Gnomad EAS AF: 0.868

Gnomad SAS AF: 0.698

Gnomad FIN AF: 0.558

Gnomad MID AF: 0.614

Gnomad NFE AF: 0.568

Gnomad OTH AF: 0.665

GnomAD4 exome AF: 0.592 AC: 824741 AN: 1392224 Hom.: 247908 Cov.: 31 AF XY: 0.595 AC XY: 407826 AN XY: 685574

Gnomad4 AFR exome AF: 0.771

Gnomad4 AMR exome AF: 0.639

Gnomad4 ASJ exome AF: 0.730

Gnomad4 EAS exome AF: 0.886

Gnomad4 SAS exome AF: 0.690

Gnomad4 FIN exome AF: 0.564

Gnomad4 NFE exome AF: 0.564

Gnomad4 OTH exome AF: 0.624

GnomAD4 genome AF: 0.649 AC: 98632 AN: 151894 Hom.: 32775 Cov.: 32 AF XY: 0.652 AC XY: 48386 AN XY: 74248

Gnomad4 AFR AF: 0.764

Gnomad4 AMR AF: 0.652

Gnomad4 ASJ AF: 0.738

Gnomad4 EAS AF: 0.869

Gnomad4 SAS AF: 0.699

Gnomad4 FIN AF: 0.558

Gnomad4 NFE AF: 0.568

Gnomad4 OTH AF: 0.668

Alfa AF: 0.584 Hom.: 23671

Bravo AF: 0.657

Asia WGS AF: 0.777 AC: 2700 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	4.5
DANN	Benign	0.59

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

Other links and lift over

dbSNP: rs2248949; hg19: chr19-50882169; COSMIC: COSV53802715; COSMIC: COSV53802715;