3-46521635-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_024512.5(LRRC2):c.953C>T(p.Pro318Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00131 in 1,612,594 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0065 (13 hom., cov: 32)
  • Exomes 𝑓: 0.00077 (18 hom.)
• Consequence: LRRC2 NM_024512.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.79

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0067184865).
• BP6: Variant 3-46521635-G-A is Benign according to our data. Variant chr3-46521635-G-A is described in ClinVar as [Benign]. Clinvar id is 708653.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00648 (987/152258) while in subpopulation AFR AF= 0.0221 (920/41538). AF 95% confidence interval is 0.021. There are 13 homozygotes in gnomad4. There are 472 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRC2	NM_024512.5	c.953C>T	p.Pro318Leu	missense_variant	8/9	ENST00000395905.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRC2	ENST00000395905.8	c.953C>T	p.Pro318Leu	missense_variant	8/9	1	NM_024512.5	P1
LRRC2	ENST00000296144.3	c.953C>T	p.Pro318Leu	missense_variant	8/9	1		P1
LRRC2	ENST00000682605.1	c.953C>T	p.Pro318Leu	missense_variant	8/9			P1

Frequencies

GnomAD3 genomes AF: 0.00642 AC: 977 AN: 152140 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.0220

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00575

GnomAD3 exomes AF: 0.00171 AC: 427 AN: 250344 Hom.: 5 AF XY: 0.00122 AC XY: 165 AN XY: 135376

Gnomad AFR exome AF: 0.0215

Gnomad AMR exome AF: 0.00163

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.000981

GnomAD4 exome AF: 0.000770 AC: 1124 AN: 1460336 Hom.: 18 Cov.: 30 AF XY: 0.000652 AC XY: 474 AN XY: 726520

Gnomad4 AFR exome AF: 0.0252

Gnomad4 AMR exome AF: 0.00193

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000270

Gnomad4 OTH exome AF: 0.00245

GnomAD4 genome AF: 0.00648 AC: 987 AN: 152258 Hom.: 13 Cov.: 32 AF XY: 0.00634 AC XY: 472 AN XY: 74450

Gnomad4 AFR AF: 0.0221

Gnomad4 AMR AF: 0.00314

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00569

Alfa AF: 0.00112 Hom.: 1

Bravo AF: 0.00771

ESP6500AA AF: 0.0209 AC: 92

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00210 AC: 255

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000237

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

Aug 10, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.45
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.037	T;T
Eigen	Benign	-0.090
Eigen_PC	Benign	-0.000075
FATHMM_MKL	Uncertain	0.91	D
MetaRNN	Benign	0.0067	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-5.5	D;D
REVEL	Benign	0.12
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.14	T;T
Polyphen		0.0030	B;B
Vest4		0.70
MVP		0.27
MPC		0.93
ClinPred		0.11	T
GERP RS		3.5
Varity_R		0.53
gMVP		0.56

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: rs150762901; hg19: chr3-46563125; COSMIC: COSV99060411;