8-104490833-C-T

Variant names:

• chr8-104490833-C-T
• NM_013437.5:c.2420G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_013437.5(LRP12):​c.2420G>A​(p.Arg807Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LRP12 NM_013437.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.46
• Publications: 0 publications found

Genes affected

LRP12 (HGNC:31708): (LDL receptor related protein 12) This gene encodes a member of the low-density lipoprotein receptor related protein family. The product of this gene is a transmembrane protein that is differentially expressed in many cancer cells. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Feb 2010]

LRP12 Gene-Disease associations (from GenCC):

• oculopharyngodistal myopathy 1

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1475246).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP12	NM_013437.5	c.2420G>A	p.Arg807Lys	missense_variant	Exon 7 of 7	ENST00000276654.10	NP_038465.1
LRP12	NM_001135703.3	c.2363G>A	p.Arg788Lys	missense_variant	Exon 6 of 6		NP_001129175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP12	ENST00000276654.10	c.2420G>A	p.Arg807Lys	missense_variant	Exon 7 of 7	1	NM_013437.5	ENSP00000276654.5
LRP12	ENST00000424843.6	c.2363G>A	p.Arg788Lys	missense_variant	Exon 6 of 6	2		ENSP00000399148.2
LRP12	ENST00000518375.1	n.1773G>A		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Mar 21, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2420G>A (p.R807K) alteration is located in exon 7 (coding exon 7) of the LRP12 gene. This alteration results from a G to A substitution at nucleotide position 2420, causing the arginine (R) at amino acid position 807 to be replaced by a lysine (K). 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	0.098
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.092	.;T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.83	T;T
M_CAP	Benign	0.0095	T
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	0.69	.;N
PhyloP100		5.5
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.45	N;N
REVEL	Benign	0.20
Sift	Benign	0.11	T;T
Sift4G	Benign	0.53	T;T
Polyphen		0.12	B;B
Vest4		0.17
MutPred		0.14		.;Gain of ubiquitination at R807 (P = 0.0037);
MVP		0.49
MPC		0.25
ClinPred		0.33	T
GERP RS		4.5
Varity_R		0.14
gMVP		0.11
Mutation Taster		=99/1	polymorphism

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

hg19: chr8-105503061;