Variant 2-140274598-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2

The NM_018557.3(LRP1B):c.12968A>G(p.Tyr4323Cys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000728 in 1,606,244 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000075 ( 0 hom. )

Consequence

LRP1B
NM_018557.3 missense, splice_region

Scores

Splicing: ADA: 0.03493

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.17

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP2

Missense variant where missense usually causes diseases, LRP1B

BS2

High AC in GnomAd at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
LRP1B	NM_018557.3 linkuse as main transcript	c.12968A>G	p.Tyr4323Cys	missense_variant, splice_region_variant	85/91	ENST00000389484.8
LRP1B	XM_017004341.2 linkuse as main transcript	c.12578A>G	p.Tyr4193Cys	missense_variant, splice_region_variant	85/91
LRP1B	XM_017004342.1 linkuse as main transcript	c.7820A>G	p.Tyr2607Cys	missense_variant, splice_region_variant	56/62

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
LRP1B	ENST00000389484.8 linkuse as main transcript	c.12968A>G	p.Tyr4323Cys	missense_variant, splice_region_variant	85/91	1	NM_018557.3	P1
LRP1B	ENST00000437977.5 linkuse as main transcript	c.1664A>G	p.Tyr555Cys	missense_variant, splice_region_variant	12/17	5
LRP1B	ENST00000442974.1 linkuse as main transcript	c.164A>G	p.Tyr55Cys	missense_variant, splice_region_variant	2/7	5

Frequencies

GnomAD3 genomes

AF:

0.0000527

AC:

AN:

151904

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000736

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000204

AC:

AN:

245416

Hom.:

AF XY:

0.0000226

AC XY:

AN XY:

132684

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000449

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000749

AC:

109

AN:

1454340

Hom.:

Cov.:

AF XY:

0.0000761

AC XY:

AN XY:

723202

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000974

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

AF:

0.0000527

AC:

AN:

151904

Hom.:

Cov.:

AF XY:

0.0000539

AC XY:

AN XY:

74144

show subpopulations

Gnomad4 AFR

AF:

0.0000725

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000736

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000314

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000551

EpiControl

AF:

0.00

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

Dec 27, 2023

The c.12968A>G (p.Y4323C) alteration is located in exon 85 (coding exon 85) of the LRP1B gene. This alteration results from a A to G substitution at nucleotide position 12968, causing the tyrosine (Y) at amino acid position 4323 to be replaced by a cysteine (C). 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

Uncertain

0.37

BayesDel_addAF

Uncertain

0.027

BayesDel_noAF

Benign

-0.090

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.11

Eigen

Uncertain

0.20

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.90

M_CAP

Uncertain

0.11

MetaRNN

Uncertain

0.73

MetaSVM

Uncertain

-0.010

MutationAssessor

Benign

1.2

MutationTaster

Benign

1.0

PrimateAI

Benign

0.48

PROVEAN

Benign

-1.1

REVEL

Uncertain

0.47

Sift

Benign

0.084

Sift4G

Uncertain

0.027

Polyphen

0.98

Vest4

0.78

MVP

0.15

MPC

0.66

ClinPred

0.76

GERP RS

5.4

Varity_R

0.13

gMVP

0.83

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.035

dbscSNV1_RF

Benign

0.35

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