1-53266643-G-T

Variant names:

• chr1-53266643-G-T
• rs2297660
• NM_004631.5:c.1257C>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4 BP7 BA1

The NM_004631.5(LRP8):​c.1257C>A​(p.Gly419Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.394 in 1,612,990 control chromosomes in the GnomAD database, including 131,104 homozygotes. In-silico tool predicts a benign 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. G419G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.36 (10586 hom., cov: 32)
  • Exomes 𝑓: 0.40 (120518 hom.)
• Consequence: LRP8 NM_004631.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.876
• Publications: 39 publications found

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]

LRP8 Gene-Disease associations (from GenCC):

• Tourette syndrome

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

LOC105378728 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.259).
• BP7: Synonymous conserved (PhyloP=0.876 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.611 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004631.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP8	NM_004631.5	MANE Select	c.1257C>A	p.Gly419Gly	synonymous	Exon 9 of 19	NP_004622.2	Q14114-1
	LRP8	NM_001018054.3		c.1257C>A	p.Gly419Gly	synonymous	Exon 9 of 18	NP_001018064.1	Q14114-3
	LRP8	NM_033300.4		c.747C>A	p.Gly249Gly	synonymous	Exon 7 of 17	NP_150643.2	Q14114-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP8	ENST00000306052.12	TSL:1 MANE Select	c.1257C>A	p.Gly419Gly	synonymous	Exon 9 of 19	ENSP00000303634.6	Q14114-1
	LRP8	ENST00000371454.6	TSL:1	c.1257C>A	p.Gly419Gly	synonymous	Exon 9 of 18	ENSP00000360509.2	Q14114-3
	LRP8	ENST00000347547.7	TSL:1	c.747C>A	p.Gly249Gly	synonymous	Exon 7 of 17	ENSP00000334522.2	Q14114-4

Frequencies

GnomAD3 genomes AF: 0.357 AC: 54273 AN: 151848 Hom.: 10584 Cov.: 32

Gnomad AFR AF: 0.229

Gnomad AMI AF: 0.500

Gnomad AMR AF: 0.359

Gnomad ASJ AF: 0.323

Gnomad EAS AF: 0.629

Gnomad SAS AF: 0.211

Gnomad FIN AF: 0.441

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.414

Gnomad OTH AF: 0.319

GnomAD2 exomes AF: 0.382 AC: 96107 AN: 251266 AF XY: 0.374

Gnomad AFR exome AF: 0.225

Gnomad AMR exome AF: 0.373

Gnomad ASJ exome AF: 0.326

Gnomad EAS exome AF: 0.643

Gnomad FIN exome AF: 0.442

Gnomad NFE exome AF: 0.411

Gnomad OTH exome AF: 0.369

GnomAD4 exome AF: 0.398 AC: 581475 AN: 1461024 Hom.: 120518 Cov.: 38 AF XY: 0.392 AC XY: 285127 AN XY: 726852

African (AFR) AF: 0.225 AC: 7524 AN: 33460

American (AMR) AF: 0.363 AC: 16244 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.323 AC: 8449 AN: 26118

East Asian (EAS) AF: 0.645 AC: 25609 AN: 39694

South Asian (SAS) AF: 0.200 AC: 17268 AN: 86230

European-Finnish (FIN) AF: 0.440 AC: 23486 AN: 53396

Middle Eastern (MID) AF: 0.244 AC: 1395 AN: 5718

European-Non Finnish (NFE) AF: 0.413 AC: 458927 AN: 1111354

Other (OTH) AF: 0.374 AC: 22573 AN: 60340

GnomAD4 genome AF: 0.357 AC: 54298 AN: 151966 Hom.: 10586 Cov.: 32 AF XY: 0.356 AC XY: 26476 AN XY: 74294

African (AFR) AF: 0.229 AC: 9477 AN: 41470

American (AMR) AF: 0.359 AC: 5476 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.323 AC: 1122 AN: 3472

East Asian (EAS) AF: 0.629 AC: 3242 AN: 5156

South Asian (SAS) AF: 0.210 AC: 1013 AN: 4816

European-Finnish (FIN) AF: 0.441 AC: 4653 AN: 10552

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.414 AC: 28116 AN: 67938

Other (OTH) AF: 0.323 AC: 680 AN: 2104

Alfa AF: 0.383 Hom.: 24789

Bravo AF: 0.350

Asia WGS AF: 0.380 AC: 1321 AN: 3478

EpiCase AF: 0.388

EpiControl AF: 0.387

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	9.5
DANN	Benign	0.86
PhyloP100		0.88
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=289/11	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2297660; hg19: chr1-53732315; COSMIC: COSV60096180; COSMIC: COSV60096180;