Variant 6-40392371-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_020737.3(LRFN2):c.1942C>T(p.Arg648Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000342 in 1,597,548 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00035 ( 0 hom. )

Consequence

LRFN2
NM_020737.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.08

Variant links:

Genes affected

LRFN2 (HGNC:21226): (leucine rich repeat and fibronectin type III domain containing 2) Predicted to be involved in modulation of chemical synaptic transmission and regulation of postsynapse organization. Predicted to be located in plasma membrane. Predicted to be active in Schaffer collateral - CA1 synapse and cell surface. Predicted to be integral component of postsynaptic density membrane. [provided by Alliance of Genome Resources, Apr 2022]

LRFN2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.12687144).

BS2

High AC in GnomAd at 37 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRFN2	NM_020737.3 linkuse as main transcript	c.1942C>T	p.Arg648Cys	missense_variant	3/3	ENST00000338305.7
LRFN2	XM_011514762.3 linkuse as main transcript	c.1942C>T	p.Arg648Cys	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRFN2	ENST00000338305.7 linkuse as main transcript	c.1942C>T	p.Arg648Cys	missense_variant	3/3	1	NM_020737.3	P1
LRFN2	ENST00000700335.1 linkuse as main transcript	c.1942C>T	p.Arg648Cys	missense_variant	4/4

Frequencies

GnomAD3 genomes

AF:

0.000243

AC:

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000411

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000219

AC:

AN:

205822

Hom.:

AF XY:

0.000256

AC XY:

AN XY:

113262

show subpopulations

Gnomad AFR exome

AF:

0.000175

Gnomad AMR exome

AF:

0.000158

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000475

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000276

Gnomad OTH exome

AF:

0.000194

GnomAD4 exome

AF:

0.000352

AC:

509

AN:

1445184

Hom.:

Cov.:

AF XY:

0.000321

AC XY:

230

AN XY:

717534

show subpopulations

Gnomad4 AFR exome

AF:

0.0000904

Gnomad4 AMR exome

AF:

0.000117

Gnomad4 ASJ exome

AF:

0.0000390

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000656

Gnomad4 FIN exome

AF:

0.0000197

Gnomad4 NFE exome

AF:

0.000388

Gnomad4 OTH exome

AF:

0.000251

GnomAD4 genome

AF:

0.000243

AC:

AN:

152364

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74512

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000412

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000336

Hom.:

Bravo

AF:

0.000298

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000357

AC:

ExAC

AF:

0.000317

AC:

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 submitter

clinical testing

Ambry Genetics

Aug 02, 2021

The c.1942C>T (p.R648C) alteration is located in exon 3 (coding exon 2) of the LRFN2 gene. This alteration results from a C to T substitution at nucleotide position 1942, causing the arginine (R) at amino acid position 648 to be replaced by a cysteine (C). 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

Uncertain

0.37

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.27

Cadd

Uncertain

Dann

Pathogenic

1.0

DEOGEN2

Benign

0.094

Eigen

Benign

0.16

Eigen_PC

Uncertain

0.22

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.83

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.13

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.3

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-1.7

REVEL

Benign

0.14

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.045

Polyphen

1.0

Vest4

0.42

MVP

0.71

MPC

0.86

ClinPred

0.19

GERP RS

4.8

Varity_R

0.14

gMVP

0.077

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over