2-140297972-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_018557.3(LRP1B):c.12806-3T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000194 in 1,585,346 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00028 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: LRP1B NM_018557.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00003940
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.595

Genes affected

LRP1B (HGNC:6693): (LDL receptor related protein 1B) This gene encodes a member of the low density lipoprotein (LDL) receptor family. These receptors play a wide variety of roles in normal cell function and development due to their interactions with multiple ligands. Disruption of this gene has been reported in several types of cancer. [provided by RefSeq, Jun 2016]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 2-140297972-A-G is Benign according to our data. Variant chr2-140297972-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 3045266.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 42 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP1B	NM_018557.3	c.12806-3T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000389484.8
LRP1B	XM_017004341.2	c.12416-3T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
LRP1B	XM_017004342.1	c.7658-3T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP1B	ENST00000389484.8	c.12806-3T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_018557.3	P1
LRP1B	ENST00000437977.5	c.1501-3T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5
LRP1B	ENST00000442974.1			upstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.000276 AC: 42 AN: 152174 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000339 AC: 82 AN: 241552 Hom.: 0 AF XY: 0.000329 AC XY: 43 AN XY: 130546

Gnomad AFR exome AF: 0.0000629

Gnomad AMR exome AF: 0.00146

Gnomad ASJ exome AF: 0.000106

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000347

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000227

Gnomad OTH exome AF: 0.00121

GnomAD4 exome AF: 0.000185 AC: 265 AN: 1433054 Hom.: 0 Cov.: 30 AF XY: 0.000200 AC XY: 142 AN XY: 710458

Gnomad4 AFR exome AF: 0.0000917

Gnomad4 AMR exome AF: 0.00139

Gnomad4 ASJ exome AF: 0.0000398

Gnomad4 EAS exome AF: 0.0000256

Gnomad4 SAS exome AF: 0.0000360

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000146

Gnomad4 OTH exome AF: 0.000475

GnomAD4 genome AF: 0.000276 AC: 42 AN: 152292 Hom.: 1 Cov.: 32 AF XY: 0.000295 AC XY: 22 AN XY: 74472

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.000981

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000229 Hom.: 0

Bravo AF: 0.000314

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

LRP1B-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 12, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.030
Dann	Benign	0.27

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000039
dbscSNV1_RF	Benign	0.012
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: rs201590927; hg19: chr2-141055541; COSMIC: COSV104431943; COSMIC: COSV104431943;