3-46521579-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_024512.5(LRRC2):c.1009C>T(p.Arg337Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000556 in 1,612,658 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R337H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0028 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00032 (3 hom.)
• Consequence: LRRC2 NM_024512.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 6.55

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006883949).
• BP6: Variant 3-46521579-G-A is Benign according to our data. Variant chr3-46521579-G-A is described in ClinVar as [Benign]. Clinvar id is 785049.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRC2	NM_024512.5	c.1009C>T	p.Arg337Cys	missense_variant	8/9	ENST00000395905.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRC2	ENST00000395905.8	c.1009C>T	p.Arg337Cys	missense_variant	8/9	1	NM_024512.5	P1
LRRC2	ENST00000296144.3	c.1009C>T	p.Arg337Cys	missense_variant	8/9	1		P1
LRRC2	ENST00000682605.1	c.1009C>T	p.Arg337Cys	missense_variant	8/9			P1

Frequencies

GnomAD3 genomes AF: 0.00281 AC: 428 AN: 152058 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00974

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000984

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.000790 AC: 198 AN: 250716 Hom.: 0 AF XY: 0.000546 AC XY: 74 AN XY: 135562

Gnomad AFR exome AF: 0.0102

Gnomad AMR exome AF: 0.000609

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000981

GnomAD4 exome AF: 0.000319 AC: 466 AN: 1460482 Hom.: 3 Cov.: 29 AF XY: 0.000289 AC XY: 210 AN XY: 726652

Gnomad4 AFR exome AF: 0.00929

Gnomad4 AMR exome AF: 0.00139

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000928

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.00114

GnomAD4 genome AF: 0.00283 AC: 431 AN: 152176 Hom.: 2 Cov.: 32 AF XY: 0.00261 AC XY: 194 AN XY: 74380

Gnomad4 AFR AF: 0.00978

Gnomad4 AMR AF: 0.000983

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000551 Hom.: 1

Bravo AF: 0.00352

ESP6500AA AF: 0.00862 AC: 38

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00101 AC: 122

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Apr 04, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.17
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Benign	0.13	T;T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.96	D
MetaRNN	Benign	0.0069	T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.5	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.48	T
PROVEAN	Uncertain	-3.2	D;D
REVEL	Benign	0.18
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.019	D;D
Polyphen		1.0	D;D
Vest4		0.70
MVP		0.43
MPC		1.0
ClinPred		0.036	T
GERP RS		4.6
Varity_R		0.14
gMVP		0.47

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

Other links and lift over

dbSNP: rs141371381; hg19: chr3-46563069; COSMIC: COSV56124758;