Genetic Variant LRFN2:p.Ala618Ser (chr6-40392461-C-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A618T) has been classified 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

Publications

3 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

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

BS2

High AC in GnomAd4 at 31 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.1852G>T	p.Ala618Ser	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.1852G>T	p.Ala618Ser	missense	Exon 3 of 3	ENSP00000345985.6	Q9ULH4
	LRFN2	ENST00000700335.1		c.1852G>T	p.Ala618Ser	missense	Exon 4 of 4	ENSP00000514953.1	A0A8V8TQ63

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

GnomAD2 exomes

AF:

0.000165

AC:

AN:

163930

AF XY:

0.000123

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 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

African (AFR)

AF:

0.0000932

AC:

AN:

32190

American (AMR)

AF:

0.0000793

AC:

AN:

37830

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25376

East Asian (EAS)

AF:

0.00

AC:

AN:

36730

South Asian (SAS)

AF:

0.00

AC:

AN:

81830

European-Finnish (FIN)

AF:

0.000103

AC:

AN:

48634

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.000481

AC:

523

AN:

1088270

Other (OTH)

AF:

0.000836

AC:

AN:

58594

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

134

179

224

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000204

AC:

AN:

152248

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.0000723

AC:

AN:

41466

American (AMR)

AF:

0.00

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000382

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000573

Hom.:

Bravo

AF:

0.000204

ExAC

AF:

0.000208

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

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

PhyloP100

3.7

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

Mutation Taster

=95/5

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

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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