Variant 2-140274518-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_SupportingBS2

The NM_018557.3(LRP1B):c.13048C>G(p.Arg4350Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000333 in 1,612,306 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00035 ( 0 hom. )

Consequence

LRP1B
NM_018557.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.30

Variant links:

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]

LRP1B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000197 (30/151922) while in subpopulation NFE AF= 0.000324 (22/67936). AF 95% confidence interval is 0.000218. There are 0 homozygotes in gnomad4. There are 11 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 30 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP1B	NM_018557.3 link	c.13048C>G	p.Arg4350Gly	missense_variant	85/91	ENST00000389484.8	NP_061027.2	Q9NZR2
LRP1B	XM_017004341.2 link	c.12658C>G	p.Arg4220Gly	missense_variant	85/91		XP_016859830.1
LRP1B	XM_017004342.1 link	c.7900C>G	p.Arg2634Gly	missense_variant	56/62		XP_016859831.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
LRP1B	ENST00000389484.8 link	c.13048C>G	p.Arg4350Gly	missense_variant	85/91	1	NM_018557.3	ENSP00000374135.3	Q9NZR2
LRP1B	ENST00000437977.5 link	c.1741C>G	p.Arg581Gly	missense_variant	12/17	5		ENSP00000415052.1	H0Y7T7
LRP1B	ENST00000442974.1 link	c.241C>G	p.Arg81Gly	missense_variant	2/7	5		ENSP00000393859.1	H7C0A8

Frequencies

GnomAD3 genomes

AF:

0.000198

AC:

AN:

151806

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000726

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000263

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000324

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000223

AC:

AN:

250854

Hom.:

AF XY:

0.000229

AC XY:

AN XY:

135566

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000414

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000347

AC:

507

AN:

1460384

Hom.:

Cov.:

AF XY:

0.000334

AC XY:

243

AN XY:

726512

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.000436

Gnomad4 OTH exome

AF:

0.0000829

GnomAD4 genome

AF:

0.000197

AC:

AN:

151922

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74242

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.000263

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000324

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000225

Hom.:

Bravo

AF:

0.000174

ExAC

AF:

0.000255

AC:

EpiCase

AF:

0.000491

EpiControl

AF:

0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 17, 2024

The c.13048C>G (p.R4350G) alteration is located in exon 85 (coding exon 85) of the LRP1B gene. This alteration results from a C to G substitution at nucleotide position 13048, causing the arginine (R) at amino acid position 4350 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

0.0082

BayesDel_noAF

Uncertain

0.10

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.066

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.89

M_CAP

Uncertain

0.11

MetaRNN

Uncertain

0.51

MetaSVM

Uncertain

0.15

MutationAssessor

Benign

0.92

PrimateAI

Uncertain

0.57

PROVEAN

Benign

0.40

REVEL

Uncertain

0.59

Sift

Benign

0.53

Sift4G

Benign

0.12

Polyphen

0.99

Vest4

0.67

MVP

0.50

MPC

0.35

ClinPred

0.046

GERP RS

5.4

Varity_R

0.34

gMVP

0.75

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over