4-185372960-G-C

Variant names:

• chr4-185372960-G-C
• rs1251158847
• NM_001377440.1:c.699C>G

Variant summary

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

The NM_001377440.1(LRP2BP):​c.699C>G​(p.Cys233Trp) variant causes a missense change involving the alteration of a non-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: LRP2BP NM_001377440.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.99
• Publications: 0 publications found

Genes affected

LRP2BP (HGNC:25434): (LRP2 binding protein) Predicted to be located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

SNX25 (HGNC:21883): (sorting nexin 25) Predicted to enable type I transforming growth factor beta receptor binding activity. Involved in negative regulation of pathway-restricted SMAD protein phosphorylation; negative regulation of transforming growth factor beta receptor signaling pathway; and receptor catabolic process. Located in intracellular membrane-bounded organelle. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001377440.1. 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
	LRP2BP	NM_001377440.1	MANE Select	c.699C>G	p.Cys233Trp	missense	Exon 7 of 9	NP_001364369.1	Q9P2M1-1
	LRP2BP	NM_001385601.1		c.699C>G	p.Cys233Trp	missense	Exon 7 of 9	NP_001372530.1	Q9P2M1-1
	LRP2BP	NM_018409.4		c.699C>G	p.Cys233Trp	missense	Exon 6 of 8	NP_060879.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP2BP	ENST00000505916.6	TSL:2 MANE Select	c.699C>G	p.Cys233Trp	missense	Exon 7 of 9	ENSP00000426203.1	Q9P2M1-1
	LRP2BP	ENST00000328559.11	TSL:1	c.699C>G	p.Cys233Trp	missense	Exon 6 of 8	ENSP00000332681.7	Q9P2M1-1
	LRP2BP	ENST00000510776.5	TSL:1	c.621C>G	p.Cys207Trp	missense	Exon 5 of 7	ENSP00000424610.1	G5E9Z9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.086	T
Eigen	Benign	-0.082
Eigen_PC	Benign	0.042
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.027	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	-1.3	N
PhyloP100		2.0
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.29
Sift	Benign	0.11	T
Sift4G	Benign	0.29	T
Polyphen		1.0	D
Vest4		0.44
MutPred		0.64		Gain of catalytic residue at L231 (P = 0.0055)
MVP		0.52
MPC		0.90
ClinPred		0.97	D
GERP RS		5.2
Varity_R		0.25
gMVP		0.73
Mutation Taster		=69/31	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

dbSNP: rs1251158847; hg19: chr4-186294114;