1-53247055-C-G

Variant names:

• chr1-53247055-C-G
• rs5174
• NM_004631.5:c.2855G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004631.5(LRP8):​c.2855G>C​(p.Arg952Pro) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R952Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LRP8 NM_004631.5 missense, splice_region
• Scores: Splicing: ADA: 0.9729
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.18

Genes affected

LRP8 (HGNC:6700): (LDL receptor related protein 8) This gene encodes a member of the low density lipoprotein receptor (LDLR) family. Low density lipoprotein receptors are cell surface proteins that play roles in both signal transduction and receptor-mediated endocytosis of specific ligands for lysosomal degradation. The encoded protein plays a critical role in the migration of neurons during development by mediating Reelin signaling, and also functions as a receptor for the cholesterol transport protein apolipoprotein E. Expression of this gene may be a marker for major depressive disorder. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jun 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP8	NM_004631.5	c.2855G>C	p.Arg952Pro	missense_variant, splice_region_variant	Exon 19 of 19	ENST00000306052.12	NP_004622.2
LRP8	NM_001018054.3	c.2678G>C	p.Arg893Pro	missense_variant, splice_region_variant	Exon 18 of 18		NP_001018064.1
LRP8	NM_033300.4	c.2345G>C	p.Arg782Pro	missense_variant, splice_region_variant	Exon 17 of 17		NP_150643.2
LRP8	NM_017522.5	c.2066G>C	p.Arg689Pro	missense_variant, splice_region_variant	Exon 16 of 16		NP_059992.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP8	ENST00000306052.12	c.2855G>C	p.Arg952Pro	missense_variant, splice_region_variant	Exon 19 of 19	1	NM_004631.5	ENSP00000303634.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.051	T;.;.;.;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.82	T;T;.;T;T
M_CAP	Uncertain	0.28	D
MetaRNN	Uncertain	0.62	D;D;D;D;D
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Benign	0.69	N;.;.;.;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.54	N;D;D;D;N
REVEL	Uncertain	0.61
Sift	Uncertain	0.0030	D;T;T;T;D
Sift4G	Pathogenic	0.0	D;T;T;T;D
Polyphen		1.0	D;P;P;D;D
Vest4		0.64
MutPred		0.23		Gain of loop (P = 0.0166);.;.;.;.;
MVP		0.93
MPC		1.4
ClinPred		0.86	D
GERP RS		5.4
Varity_R		0.33
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Pathogenic	0.85
SpliceAI score (max)		0.060		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: rs5174; hg19: chr1-53712727;