2-140510004-G-C

Position:

• chr2-140510004-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Strong

The NM_018557.3(LRP1B):​c.8322C>G​(p.Cys2774Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. C2774C) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LRP1B NM_018557.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0130

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, LRP1B
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP1B	NM_018557.3	c.8322C>G	p.Cys2774Trp	missense_variant	52/91	ENST00000389484.8
LRP1B	XM_017004341.2	c.7932C>G	p.Cys2644Trp	missense_variant	52/91
LRP1B	XM_047444771.1	c.8433C>G	p.Cys2811Trp	missense_variant	52/77
LRP1B	XM_017004342.1	c.3174C>G	p.Cys1058Trp	missense_variant	23/62

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP1B	ENST00000389484.8	c.8322C>G	p.Cys2774Trp	missense_variant	52/91	1	NM_018557.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.91	D
Eigen	Benign	0.073
Eigen_PC	Benign	-0.092
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	4.6	H
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-9.4	D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.97		Loss of disorder (P = 0.0255);
MVP		0.65
MPC		0.83
ClinPred		1.0	D
GERP RS		-1.7
Varity_R		0.95
gMVP		0.98

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-141267573;