2-140233187-T-C

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.13799A>G(p.Ter4600=) variant causes a stop retained change. The variant allele was found at a frequency of 0.000332 in 1,586,566 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00025 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (1 hom.)
• Consequence: LRP1B NM_018557.3 stop_retained
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.95

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=-0.48).
• BP6: Variant 2-140233187-T-C is Benign according to our data. Variant chr2-140233187-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 3053649.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 40 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP1B	NM_018557.3	c.13799A>G	p.Ter4600=	stop_retained_variant	91/91	ENST00000389484.8
LRP1B	XM_017004341.2	c.13409A>G	p.Ter4470=	stop_retained_variant	91/91
LRP1B	XM_017004342.1	c.8651A>G	p.Ter2884=	stop_retained_variant	62/62

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP1B	ENST00000389484.8	c.13799A>G	p.Ter4600=	stop_retained_variant	91/91	1	NM_018557.3	P1
LRP1B	ENST00000437977.5	c.2396A>G	p.Ter799=	stop_retained_variant	17/17	5

Frequencies

GnomAD3 genomes AF: 0.000264 AC: 40 AN: 151312 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000196

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000400

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000259 AC: 63 AN: 242904 Hom.: 1 AF XY: 0.000312 AC XY: 41 AN XY: 131614

Gnomad AFR exome AF: 0.000127

Gnomad AMR exome AF: 0.000151

Gnomad ASJ exome AF: 0.000207

Gnomad EAS exome AF: 0.0000566

Gnomad SAS exome AF: 0.000272

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000389

Gnomad OTH exome AF: 0.000342

GnomAD4 exome AF: 0.000340 AC: 488 AN: 1435136 Hom.: 1 Cov.: 27 AF XY: 0.000327 AC XY: 234 AN XY: 715140

Gnomad4 AFR exome AF: 0.000123

Gnomad4 AMR exome AF: 0.000161

Gnomad4 ASJ exome AF: 0.000431

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000438

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000352

Gnomad4 OTH exome AF: 0.000456

GnomAD4 genome AF: 0.000251 AC: 38 AN: 151430 Hom.: 1 Cov.: 32 AF XY: 0.000203 AC XY: 15 AN XY: 73978

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.000132

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000196

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000385

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000571 Hom.: 2

Bravo AF: 0.000200

Asia WGS AF: 0.000289 AC: 1 AN: 3472

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

Apr 26, 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	-0.48
Cadd	Benign	7.7
Dann	Benign	0.68

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: rs142353749; hg19: chr2-140990756; COSMIC: COSV104431765; COSMIC: COSV104431765;