chr3-46521558-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_024512.5(LRRC2):​c.1030G>A​(p.Val344Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,612,280 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

LRRC2
NM_024512.5 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.64
Variant links:
Genes affected
LRRC2 (HGNC:14676): (leucine rich repeat containing 2) This gene encodes a member of the leucine-rich repeat-containing family of proteins, which function in diverse biological pathways. This family member may possibly be a nuclear protein. Similarity to the RAS suppressor protein, as well as expression down-regulation observed in tumor cells, suggests that it may function as a tumor suppressor. The gene is located in the chromosome 3 common eliminated region 1 (C3CER1), a 1.4 Mb region that is commonly deleted in diverse tumors. A related pseudogene has been identified on chromosome 2. [provided by RefSeq, Sep 2011]

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ACMG classification

Classification made for transcript

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=0.011996239).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
LRRC2NM_024512.5 linkuse as main transcriptc.1030G>A p.Val344Ile missense_variant 8/9 ENST00000395905.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
LRRC2ENST00000395905.8 linkuse as main transcriptc.1030G>A p.Val344Ile missense_variant 8/91 NM_024512.5 P1
LRRC2ENST00000296144.3 linkuse as main transcriptc.1030G>A p.Val344Ile missense_variant 8/91 P1
LRRC2ENST00000682605.1 linkuse as main transcriptc.1030G>A p.Val344Ile missense_variant 8/9 P1

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152158
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000577
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000840
AC:
21
AN:
249912
Hom.:
0
AF XY:
0.0000962
AC XY:
13
AN XY:
135140
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00114
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000130
AC:
19
AN:
1460004
Hom.:
0
Cov.:
29
AF XY:
0.0000179
AC XY:
13
AN XY:
726378
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000454
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152276
Hom.:
0
Cov.:
32
AF XY:
0.0000403
AC XY:
3
AN XY:
74468
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000578
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000473
Bravo
AF:
0.0000227
ExAC
AF:
0.0000906
AC:
11

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsAug 11, 2022The c.1030G>A (p.V344I) alteration is located in exon 8 (coding exon 7) of the LRRC2 gene. This alteration results from a G to A substitution at nucleotide position 1030, causing the valine (V) at amino acid position 344 to be replaced by an isoleucine (I). 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
0.097
BayesDel_addAF
Benign
-0.61
T
BayesDel_noAF
Benign
-0.71
CADD
Benign
18
DANN
Benign
0.97
DEOGEN2
Benign
0.0011
T;T
Eigen
Benign
-0.64
Eigen_PC
Benign
-0.45
FATHMM_MKL
Benign
0.70
D
LIST_S2
Benign
0.78
.;T
M_CAP
Benign
0.0053
T
MetaRNN
Benign
0.012
T;T
MetaSVM
Benign
-0.98
T
MutationAssessor
Benign
-0.20
N;N
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.46
T
PROVEAN
Benign
0.46
N;N
REVEL
Benign
0.025
Sift
Benign
0.11
T;T
Sift4G
Benign
0.14
T;T
Polyphen
0.0030
B;B
Vest4
0.17
MVP
0.076
MPC
0.22
ClinPred
0.097
T
GERP RS
2.2
Varity_R
0.031
gMVP
0.29

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs201560633; hg19: chr3-46563048; API