Variant 6-40392413-C-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.1900G>T(p.Gly634Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000829 in 1,568,642 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000064 ( 0 hom. )

Consequence

LRFN2
NM_020737.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.34

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=0.14887846).

BS2

High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRFN2	NM_020737.3 link	c.1900G>T	p.Gly634Trp	missense_variant	3/3	ENST00000338305.7	NP_065788.1	Q9ULH4
LRFN2	XM_011514762.3 link	c.1900G>T	p.Gly634Trp	missense_variant	3/3		XP_011513064.1	Q9ULH4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRFN2	ENST00000338305.7 link	c.1900G>T	p.Gly634Trp	missense_variant	3/3	1	NM_020737.3	ENSP00000345985.6		Q9ULH4
LRFN2	ENST00000700335.1 link	c.1900G>T	p.Gly634Trp	missense_variant	4/4			ENSP00000514953.1		A0A8V8TQ63

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

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:

0.00

GnomAD3 exomes

AF:

0.0000370

AC:

AN:

162192

Hom.:

AF XY:

0.0000226

AC XY:

AN XY:

88652

show subpopulations

Gnomad AFR exome

AF:

0.000499

Gnomad AMR exome

AF:

0.0000753

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000635

AC:

AN:

1416276

Hom.:

Cov.:

AF XY:

0.00000428

AC XY:

AN XY:

700688

show subpopulations

Gnomad4 AFR exome

AF:

0.000186

Gnomad4 AMR exome

AF:

0.0000785

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152366

Hom.:

Cov.:

AF XY:

0.0000268

AC XY:

AN XY:

74510

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000756

ExAC

AF:

0.00000863

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

Oct 20, 2024

The c.1900G>T (p.G634W) 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 1900, causing the glycine (G) at amino acid position 634 to be replaced by a tryptophan (W). 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

0.15

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.32

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.079

Eigen

Benign

0.093

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.63

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.15

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-1.2

REVEL

Benign

0.12

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.011

Polyphen

0.96

Vest4

0.33

MVP

0.73

MPC

0.83

ClinPred

0.097

GERP RS

4.6

Varity_R

0.17

gMVP

0.096

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