2-140314950-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2 BP4_Strong BP6_Moderate BS2

The NM_018557.3(LRP1B):c.12790G>A(p.Val4264Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000157 in 1,603,940 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V4264L) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (3 hom.)
• Consequence: LRP1B NM_018557.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.402

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 -9 ACMG points.

• PP2: Missense variant where missense usually causes diseases, LRP1B
• BP4: Computational evidence support a benign effect (MetaRNN=0.012599349).
• BP6: Variant 2-140314950-C-T is Benign according to our data. Variant chr2-140314950-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3041230.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP1B	NM_018557.3	c.12790G>A	p.Val4264Ile	missense_variant	83/91	ENST00000389484.8
LRP1B	XM_017004341.2	c.12400G>A	p.Val4134Ile	missense_variant	83/91
LRP1B	XM_017004342.1	c.7642G>A	p.Val2548Ile	missense_variant	54/62

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP1B	ENST00000389484.8	c.12790G>A	p.Val4264Ile	missense_variant	83/91	1	NM_018557.3	P1
LRP1B	ENST00000437977.5	c.1486G>A	p.Val496Ile	missense_variant	10/17	5

Frequencies

GnomAD3 genomes AF: 0.000178 AC: 27 AN: 152034 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000354 AC: 87 AN: 245518 Hom.: 2 AF XY: 0.000377 AC XY: 50 AN XY: 132728

Gnomad AFR exome AF: 0.000812

Gnomad AMR exome AF: 0.0000609

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.00220

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000537

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000152 AC: 220 AN: 1451788 Hom.: 3 Cov.: 30 AF XY: 0.000202 AC XY: 146 AN XY: 721874

Gnomad4 AFR exome AF: 0.000725

Gnomad4 AMR exome AF: 0.0000460

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000764

Gnomad4 SAS exome AF: 0.00177

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000253

Gnomad4 OTH exome AF: 0.000234

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152152 Hom.: 0 Cov.: 32 AF XY: 0.000309 AC XY: 23 AN XY: 74362

Gnomad4 AFR AF: 0.000506

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000398 Hom.: 11

Bravo AF: 0.000155

ExAC AF: 0.000395 AC: 48

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

Feb 28, 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
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	0.52
Dann	Benign	0.38
DEOGEN2	Benign	0.25	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0058	N
LIST_S2	Benign	0.033	T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	0.27	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.22	N
REVEL	Benign	0.28
Sift	Benign	0.64	T
Sift4G	Benign	0.068	T
Polyphen		0.0	B
Vest4		0.039
MutPred		0.43		Loss of glycosylation at T4262 (P = 0.0821);
MVP		0.28
MPC		0.15
ClinPred		0.0052	T
GERP RS		0.64
Varity_R		0.021
gMVP		0.059

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: rs17386226; hg19: chr2-141072519; COSMIC: COSV67277167;