Genetic Variant NM_020737.3:c.1787C>G (chr6-40392526-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_020737.3(LRFN2):c.1787C>G(p.Pro596Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000189 in 1,588,400 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P596L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 1 hom., cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

LRFN2
NM_020737.3 missense

Scores

Clinical Significance

Not reported in ClinVar

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08066538).

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>G	p.Pro596Arg	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>G	p.Pro596Arg	missense	Exon 3 of 3	ENSP00000345985.6	Q9ULH4
	LRFN2	ENST00000700335.1		c.1787C>G	p.Pro596Arg	missense	Exon 4 of 4	ENSP00000514953.1	A0A8V8TQ63

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000958

GnomAD4 exome

AF:

6.96e-7

AC:

AN:

1436176

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

713618

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32848

American (AMR)

AF:

0.00

AC:

AN:

42016

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25770

East Asian (EAS)

AF:

0.00

AC:

AN:

38122

South Asian (SAS)

AF:

0.00

AC:

AN:

84532

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45354

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

9.07e-7

AC:

AN:

1102366

Other (OTH)

AF:

0.00

AC:

AN:

59436

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41470

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68042

Other (OTH)

AF:

0.000958

AC:

AN:

2088

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.44

CADD

Benign

6.7

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.20

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.44

LIST_S2

Benign

0.37

M_CAP

Benign

0.064

MetaRNN

Benign

0.081

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

PhyloP100

0.65

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.5

REVEL

Benign

0.063

Sift

Benign

0.23

Sift4G

Benign

0.11

Polyphen

0.086

Vest4

0.16

MutPred

0.20

Loss of catalytic residue at P595 (P = 0.0144)

MVP

0.32

MPC

0.74

ClinPred

0.13

GERP RS

-1.3

Varity_R

0.041

gMVP

0.26

Mutation Taster

=98/2

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over