Genetic Variant LRRC2:p.Met315Val (chr3-46521645-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_024512.5(LRRC2):c.943A>G(p.Met315Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000212 in 1,458,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

LRRC2
NM_024512.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.959

Publications

0 publications found

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]

LRRC2 links:

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ACMG classification

Classification was made for transcript

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=0.08399224).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRC2	NM_024512.5 link	c.943A>G	p.Met315Val	missense_variant	Exon 8 of 9	ENST00000395905.8	NP_078788.2	Q9BYS8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LRRC2	ENST00000395905.8 link	c.943A>G	p.Met315Val	missense_variant	Exon 8 of 9	1	NM_024512.5	ENSP00000379241.3	Q9BYS8
LRRC2	ENST00000296144.3 link	c.943A>G	p.Met315Val	missense_variant	Exon 8 of 9	1		ENSP00000296144.3	Q9BYS8
LRRC2	ENST00000682605.1 link	c.943A>G	p.Met315Val	missense_variant	Exon 8 of 9			ENSP00000507018.1	Q9BYS8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000401

AC:

AN:

249346

AF XY:

0.00000742

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000212

AC:

AN:

1458866

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

725700

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33350

American (AMR)

AF:

0.00

AC:

AN:

44348

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26076

East Asian (EAS)

AF:

0.00

AC:

AN:

39664

South Asian (SAS)

AF:

0.0000116

AC:

AN:

85878

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52034

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0000243

AC:

AN:

1111442

Other (OTH)

AF:

0.0000332

AC:

AN:

60314

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 11, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.943A>G (p.M315V) alteration is located in exon 8 (coding exon 7) of the LRRC2 gene. This alteration results from a A to G substitution at nucleotide position 943, causing the methionine (M) at amino acid position 315 to be replaced by a valine (V). 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

0.093

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.0033

T;T

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.43

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.58

.;T

M_CAP

Benign

0.0034

MetaRNN

Benign

0.084

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

L;L

PhyloP100

0.96

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.1

N;N

REVEL

Benign

0.029

Sift

Benign

0.19

T;T

Sift4G

Benign

0.36

T;T

Polyphen

0.0

B;B

Vest4

0.19

MutPred

0.44

Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);

MVP

0.055

MPC

0.26

ClinPred

0.043

GERP RS

1.9

Varity_R

0.047

gMVP

0.29

Mutation Taster

=92/8

polymorphism

(source)

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

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chr3-46521645-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over