chr19-50378912-A-G

Variant names:

• chr19-50378912-A-G
• rs2248949
• NM_007121.7:c.748-90A>G

Variant summary

Our verdict is Benign. The variant received -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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
NR1H2	NM_007121.7	c.748-90A>G		intron_variant	Intron 6 of 9	ENST00000253727.10	NP_009052.4
NR1H2	NM_001256647.3	c.457-90A>G		intron_variant	Intron 5 of 8		NP_001243576.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR1H2	ENST00000253727.10	c.748-90A>G		intron_variant	Intron 6 of 9	1	NM_007121.7	ENSP00000253727.4

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 AC: 24465 AN: 31742

Gnomad4 AMR exome AF: 0.639 AC: 24327 AN: 38044

Gnomad4 ASJ exome AF: 0.730 AC: 15829 AN: 21684

Gnomad4 EAS exome AF: 0.886 AC: 34678 AN: 39150

Gnomad4 SAS exome AF: 0.690 AC: 52197 AN: 75646

Gnomad4 FIN exome AF: 0.564 AC: 27353 AN: 48472

Gnomad4 NFE exome AF: 0.564 AC: 606604 AN: 1074790

Gnomad4 Remaining exome AF: 0.624 AC: 35747 AN: 57318

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 AC: 0.763643 AN: 0.763643

Gnomad4 AMR AF: 0.652 AC: 0.651547 AN: 0.651547

Gnomad4 ASJ AF: 0.738 AC: 0.738466 AN: 0.738466

Gnomad4 EAS AF: 0.869 AC: 0.868523 AN: 0.868523

Gnomad4 SAS AF: 0.699 AC: 0.69892 AN: 0.69892

Gnomad4 FIN AF: 0.558 AC: 0.557959 AN: 0.557959

Gnomad4 NFE AF: 0.568 AC: 0.568268 AN: 0.568268

Gnomad4 OTH AF: 0.668 AC: 0.667616 AN: 0.667616

Alfa AF: 0.586 Hom.: 36913

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
Mutation Taster		=99/1	polymorphism (auto)

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;