4-185370805-G-C

Position:

• chr4-185370805-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001377440.1(LRP2BP):​c.813C>G​(p.Asp271Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,461,830 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: LRP2BP NM_001377440.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.346

Genes affected

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

LRP2BP-AS1 (HGNC:55998): (LRP2BP antisense RNA 1)

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.066319704).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP2BP	NM_001377440.1	c.813C>G	p.Asp271Glu	missense_variant	8/9	ENST00000505916.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP2BP	ENST00000505916.6	c.813C>G	p.Asp271Glu	missense_variant	8/9	2	NM_001377440.1	P1
LRP2BP	ENST00000328559.11	c.813C>G	p.Asp271Glu	missense_variant	7/8	1		P1
LRP2BP	ENST00000510776.5	c.735C>G	p.Asp245Glu	missense_variant	6/7	1
LRP2BP-AS1	ENST00000514884.1	n.81G>C		non_coding_transcript_exon_variant	1/3	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1461830 Hom.: 0 Cov.: 30 AF XY: 0.00000963 AC XY: 7 AN XY: 727222

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 01, 2022

The c.813C>G (p.D271E) alteration is located in exon 7 (coding exon 7) of the LRP2BP gene. This alteration results from a C to G substitution at nucleotide position 813, causing the aspartic acid (D) at amino acid position 271 to be replaced by a glutamic acid (E). 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	0.10
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	5.3
DANN	Benign	0.61
DEOGEN2	Benign	0.055	T;.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.62	D
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.066	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.12	N;.;N
MutationTaster	Benign	0.57	D;D;D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.21	N;N;N
REVEL	Benign	0.028
Sift	Benign	0.45	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0050	B;B;B
Vest4		0.14
MutPred		0.34		Gain of glycosylation at Y272 (P = 0.0288);.;Gain of glycosylation at Y272 (P = 0.0288);
MVP		0.23
MPC		0.19
ClinPred		0.082	T
GERP RS		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.024
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs2095412192; hg19: chr4-186291959;