2-140314950-C-G

Position:

• chr2-140314950-C-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2 BP4_Strong BP6_Moderate BS1 BS2

The NM_018557.3(LRP1B):​c.12790G>C​(p.Val4264Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0168 in 1,603,762 control chromosomes in the GnomAD database, including 308 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V4264I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.020 (39 hom., cov: 32)
  • Exomes 𝑓: 0.016 (269 hom.)
• Consequence: LRP1B NM_018557.3 missense
• Clinical Significance: 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 -13 ACMG points.

• PP2: Missense variant where missense usually causes diseases, LRP1B
• BP4: Computational evidence support a benign effect (MetaRNN=0.0050440133).
• BP6: Variant 2-140314950-C-G is Benign according to our data. Variant chr2-140314950-C-G is described in ClinVar as [Benign]. Clinvar id is 3055421.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0204 (3100/152142) while in subpopulation AFR AF= 0.0283 (1173/41512). AF 95% confidence interval is 0.0269. There are 39 homozygotes in gnomad4. There are 1505 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 3100 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP1B	NM_018557.3	c.12790G>C	p.Val4264Leu	missense_variant	83/91	ENST00000389484.8
LRP1B	XM_017004341.2	c.12400G>C	p.Val4134Leu	missense_variant	83/91
LRP1B	XM_017004342.1	c.7642G>C	p.Val2548Leu	missense_variant	54/62

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP1B	ENST00000389484.8	c.12790G>C	p.Val4264Leu	missense_variant	83/91	1	NM_018557.3	P1
LRP1B	ENST00000437977.5	c.1486G>C	p.Val496Leu	missense_variant	10/17	5

Frequencies

GnomAD3 genomes AF: 0.0204 AC: 3095 AN: 152024 Hom.: 39 Cov.: 32

Gnomad AFR AF: 0.0282

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0108

Gnomad ASJ AF: 0.0260

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00767

Gnomad FIN AF: 0.0189

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0205

Gnomad OTH AF: 0.0134

GnomAD3 exomes AF: 0.0157 AC: 3849 AN: 245518 Hom.: 44 AF XY: 0.0155 AC XY: 2061 AN XY: 132728

Gnomad AFR exome AF: 0.0284

Gnomad AMR exome AF: 0.00609

Gnomad ASJ exome AF: 0.0290

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00858

Gnomad FIN exome AF: 0.0191

Gnomad NFE exome AF: 0.0193

Gnomad OTH exome AF: 0.0148

GnomAD4 exome AF: 0.0165 AC: 23882 AN: 1451620 Hom.: 269 Cov.: 30 AF XY: 0.0164 AC XY: 11863 AN XY: 721800

Gnomad4 AFR exome AF: 0.0293

Gnomad4 AMR exome AF: 0.00669

Gnomad4 ASJ exome AF: 0.0260

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00821

Gnomad4 FIN exome AF: 0.0204

Gnomad4 NFE exome AF: 0.0172

Gnomad4 OTH exome AF: 0.0180

GnomAD4 genome AF: 0.0204 AC: 3100 AN: 152142 Hom.: 39 Cov.: 32 AF XY: 0.0202 AC XY: 1505 AN XY: 74356

Gnomad4 AFR AF: 0.0283

Gnomad4 AMR AF: 0.0108

Gnomad4 ASJ AF: 0.0260

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00747

Gnomad4 FIN AF: 0.0189

Gnomad4 NFE AF: 0.0205

Gnomad4 OTH AF: 0.0133

Alfa AF: 0.0180 Hom.: 11

Bravo AF: 0.0192

TwinsUK AF: 0.0173 AC: 64

ALSPAC AF: 0.0182 AC: 70

ESP6500AA AF: 0.0266 AC: 117

ESP6500EA AF: 0.0179 AC: 154

ExAC AF: 0.0161 AC: 1950

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

LRP1B-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 23, 2019

This variant is classified as 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	0.067
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	0.10
DANN	Benign	0.40
DEOGEN2	Benign	0.29	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.015	T
MetaRNN	Benign	0.0050	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	-0.085	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.0	N
REVEL	Benign	0.28
Sift	Benign	0.59	T
Sift4G	Uncertain	0.050	T
Polyphen		0.0010	B
Vest4		0.10
MutPred		0.30		Loss of glycosylation at T4262 (P = 0.1496);
MPC		0.18
ClinPred		0.0013	T
GERP RS		0.64
Varity_R		0.032
gMVP		0.11

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: COSV104431850;