chr8-104491227-G-A

Variant names:

• chr8-104491227-G-A
• NM_013437.5:c.2026C>T

Variant summary

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

The NM_013437.5(LRP12):​c.2026C>T​(p.Pro676Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 9.10
• 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 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
LRP12	NM_013437.5	c.2026C>T	p.Pro676Ser	missense_variant	Exon 7 of 7	ENST00000276654.10	NP_038465.1
LRP12	NM_001135703.3	c.1969C>T	p.Pro657Ser	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.2026C>T	p.Pro676Ser	missense_variant	Exon 7 of 7	1	NM_013437.5	ENSP00000276654.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

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

Apr 12, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2026C>T (p.P676S) alteration is located in exon 7 (coding exon 7) of the LRP12 gene. This alteration results from a C to T substitution at nucleotide position 2026, causing the proline (P) at amino acid position 676 to be replaced by a serine (S). 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	0.26
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	.;T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.60	D;D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Benign	1.4	.;L
PhyloP100		9.1
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-2.4	N;N
REVEL	Uncertain	0.51
Sift	Uncertain	0.021	D;D
Sift4G	Benign	0.097	T;T
Polyphen		1.0	D;D
Vest4		0.61
MutPred		0.096		.;Gain of glycosylation at P676 (P = 0.021);
MVP		0.60
MPC		0.87
ClinPred		0.85	D
GERP RS		5.5
Varity_R		0.15
gMVP		0.40
Mutation Taster		=29/71	disease causing

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: chr8-105503455;