Variant 6-40392461-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_020737.3(LRFN2):c.1852G>T(p.Ala618Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000392 in 1,567,400 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00041 ( 1 hom. )

Consequence

LRFN2
NM_020737.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.71

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 Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.030613005).

BS2

High AC in GnomAd at 31 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRFN2	NM_020737.3 linkuse as main transcript	c.1852G>T	p.Ala618Ser	missense_variant	3/3	ENST00000338305.7
LRFN2	XM_011514762.3 linkuse as main transcript	c.1852G>T	p.Ala618Ser	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRFN2	ENST00000338305.7 linkuse as main transcript	c.1852G>T	p.Ala618Ser	missense_variant	3/3	1	NM_020737.3	P1
LRFN2	ENST00000700335.1 linkuse as main transcript	c.1852G>T	p.Ala618Ser	missense_variant	4/4

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000723

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000382

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000165

AC:

AN:

163930

Hom.:

AF XY:

0.000123

AC XY:

AN XY:

89664

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000378

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000636

Gnomad NFE exome

AF:

0.000346

Gnomad OTH exome

AF:

0.000665

GnomAD4 exome

AF:

0.000412

AC:

583

AN:

1415152

Hom.:

Cov.:

AF XY:

0.000371

AC XY:

260

AN XY:

700296

show subpopulations

Gnomad4 AFR exome

AF:

0.0000932

Gnomad4 AMR exome

AF:

0.0000793

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000103

Gnomad4 NFE exome

AF:

0.000481

Gnomad4 OTH exome

AF:

0.000836

GnomAD4 genome

AF:

0.000204

AC:

AN:

152248

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.0000723

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.000382

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000136

Hom.:

Bravo

AF:

0.000204

ExAC

AF:

0.000208

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

Feb 16, 2023

The c.1852G>T (p.A618S) alteration is located in exon 3 (coding exon 2) of the LRFN2 gene. This alteration results from a G to T substitution at nucleotide position 1852, causing the alanine (A) at amino acid position 618 to be replaced by a serine (S). 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

0.065

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.62

Cadd

Benign

Dann

Benign

0.24

DEOGEN2

Benign

0.050

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.74

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.61

M_CAP

Benign

0.0073

MetaRNN

Benign

0.031

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-1.5

MutationTaster

Benign

0.99

PrimateAI

Uncertain

0.54

PROVEAN

Benign

0.63

REVEL

Benign

0.14

Sift

Benign

0.90

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.044

MutPred

0.14

Gain of phosphorylation at A618 (P = 0.0026);

MVP

0.46

MPC

0.30

ClinPred

0.038

GERP RS

2.8

Varity_R

0.047

gMVP

0.057

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