Genetic Variant LRFN2:p.Pro596Leu (chr6-40392526-G-A) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_020737.3(LRFN2):c.1787C>T(p.Pro596Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00332 in 1,588,518 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0035 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0033 ( 24 hom. )

Consequence

LRFN2
NM_020737.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.647

Publications

1 publications found

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 was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00382787).

BP6

Variant 6-40392526-G-A is Benign according to our data. Variant chr6-40392526-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2656538.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 526 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020737.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRFN2	NM_020737.3	MANE Select	c.1787C>T	p.Pro596Leu	missense	Exon 3 of 3	NP_065788.1	Q9ULH4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRFN2	ENST00000338305.7	TSL:1 MANE Select	c.1787C>T	p.Pro596Leu	missense	Exon 3 of 3	ENSP00000345985.6	Q9ULH4
	LRFN2	ENST00000700335.1		c.1787C>T	p.Pro596Leu	missense	Exon 4 of 4	ENSP00000514953.1	A0A8V8TQ63

Frequencies

GnomAD3 genomes

AF:

0.00346

AC:

526

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00157

Gnomad ASJ

AF:

0.00662

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.0187

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00363

Gnomad OTH

AF:

0.00192

GnomAD2 exomes

AF:

0.00430

AC:

872

AN:

202814

AF XY:

0.00453

show subpopulations

Gnomad AFR exome

AF:

0.000261

Gnomad AMR exome

AF:

0.00128

Gnomad ASJ exome

AF:

0.00635

Gnomad EAS exome

AF:

0.000132

Gnomad FIN exome

AF:

0.0190

Gnomad NFE exome

AF:

0.00404

Gnomad OTH exome

AF:

0.00382

GnomAD4 exome

AF:

0.00331

AC:

4749

AN:

1436176

Hom.:

Cov.:

AF XY:

0.00340

AC XY:

2426

AN XY:

713618

show subpopulations

African (AFR)

AF:

0.000426

AC:

AN:

32848

American (AMR)

AF:

0.00121

AC:

AN:

42016

Ashkenazi Jewish (ASJ)

AF:

0.00508

AC:

131

AN:

25770

East Asian (EAS)

AF:

0.000105

AC:

AN:

38122

South Asian (SAS)

AF:

0.00517

AC:

437

AN:

84532

European-Finnish (FIN)

AF:

0.0187

AC:

847

AN:

45354

Middle Eastern (MID)

AF:

0.00401

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

0.00277

AC:

3054

AN:

1102366

Other (OTH)

AF:

0.00316

AC:

188

AN:

59436

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

316

631

947

1262

1578

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

196

294

392

490

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00345

AC:

526

AN:

152342

Hom.:

Cov.:

AF XY:

0.00400

AC XY:

298

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.000385

AC:

AN:

41592

American (AMR)

AF:

0.00157

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00662

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.00269

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0187

AC:

199

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00363

AC:

247

AN:

68034

Other (OTH)

AF:

0.00190

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

124

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00314

Hom.:

Bravo

AF:

0.00196

ESP6500AA

AF:

0.000255

AC:

ESP6500EA

AF:

0.00329

AC:

ExAC

AF:

0.00404

AC:

474

Asia WGS

AF:

0.00491

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.59

CADD

Benign

0.84

(source)

DANN

Benign

0.89

DEOGEN2

Uncertain

0.47

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.44

MetaRNN

Benign

0.0038

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

PhyloP100

0.65

PrimateAI

Benign

0.36

PROVEAN

Benign

-2.2

REVEL

Benign

0.064

Sift

Benign

0.20

Sift4G

Benign

0.085

Polyphen

0.0

Vest4

0.049

MVP

0.38

MPC

0.39

ClinPred

0.0018

GERP RS

-1.3

Varity_R

0.031

gMVP

0.19

Mutation Taster

=100/0

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over