3-46532867-T-G

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.533A>C(p.Tyr178Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000919 in 1,614,010 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0045 (11 hom., cov: 32)
  • Exomes 𝑓: 0.00055 (1 hom.)
• Consequence: LRRC2 NM_024512.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0300

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=0.008144259).
• BP6: Variant 3-46532867-T-G is Benign according to our data. Variant chr3-46532867-T-G is described in ClinVar as [Benign]. Clinvar id is 731673.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.000545 (797/1461668) while in subpopulation AFR AF= 0.0161 (540/33468). AF 95% confidence interval is 0.015. There are 1 homozygotes in gnomad4_exome. There are 359 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRC2	NM_024512.5	c.533A>C	p.Tyr178Ser	missense_variant	5/9	ENST00000395905.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRC2	ENST00000395905.8	c.533A>C	p.Tyr178Ser	missense_variant	5/9	1	NM_024512.5	P1
LRRC2	ENST00000296144.3	c.533A>C	p.Tyr178Ser	missense_variant	5/9	1		P1
LRRC2	ENST00000682605.1	c.533A>C	p.Tyr178Ser	missense_variant	5/9			P1

Frequencies

GnomAD3 genomes AF: 0.00450 AC: 685 AN: 152224 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.0154

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00128 AC: 321 AN: 251276 Hom.: 2 AF XY: 0.00104 AC XY: 141 AN XY: 135798

Gnomad AFR exome AF: 0.0156

Gnomad AMR exome AF: 0.00133

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: 0.0000968

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000545 AC: 797 AN: 1461668 Hom.: 1 Cov.: 33 AF XY: 0.000494 AC XY: 359 AN XY: 727130

Gnomad4 AFR exome AF: 0.0161

Gnomad4 AMR exome AF: 0.00132

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000782

Gnomad4 OTH exome AF: 0.00154

GnomAD4 genome AF: 0.00451 AC: 687 AN: 152342 Hom.: 11 Cov.: 32 AF XY: 0.00460 AC XY: 343 AN XY: 74500

Gnomad4 AFR AF: 0.0155

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00105 Hom.: 3

Bravo AF: 0.00524

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0132 AC: 58

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00147 AC: 179

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

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	0.073
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	13
Dann	Benign	0.94
DEOGEN2	Benign	0.000025	T;T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.22	N
MetaRNN	Benign	0.0081	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.60	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.81	N;N
REVEL	Benign	0.037
Sift	Uncertain	0.024	D;D
Sift4G	Benign	0.24	T;T
Polyphen		0.022	B;B
Vest4		0.17
MVP		0.095
MPC		0.38
ClinPred		0.042	T
GERP RS		-1.1
Varity_R		0.093
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

Other links and lift over

dbSNP: rs115132856; hg19: chr3-46574357;