6-40392526-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

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. 15/20 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
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.647

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 2656538.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 526 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRFN2	NM_020737.3	c.1787C>T	p.Pro596Leu	missense_variant	3/3	ENST00000338305.7
LRFN2	XM_011514762.3	c.1787C>T	p.Pro596Leu	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRFN2	ENST00000338305.7	c.1787C>T	p.Pro596Leu	missense_variant	3/3	1	NM_020737.3	P1
LRFN2	ENST00000700335.1	c.1787C>T	p.Pro596Leu	missense_variant	4/4

Frequencies

GnomAD3 genomes AF: 0.00346 AC: 526 AN: 152224 Hom.: 4 Cov.: 32

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

GnomAD3 exomes AF: 0.00430 AC: 872 AN: 202814 Hom.: 4 AF XY: 0.00453 AC XY: 511 AN XY: 112700

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 SAS exome AF: 0.00401

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.: 24 Cov.: 34 AF XY: 0.00340 AC XY: 2426 AN XY: 713618

Gnomad4 AFR exome AF: 0.000426

Gnomad4 AMR exome AF: 0.00121

Gnomad4 ASJ exome AF: 0.00508

Gnomad4 EAS exome AF: 0.000105

Gnomad4 SAS exome AF: 0.00517

Gnomad4 FIN exome AF: 0.0187

Gnomad4 NFE exome AF: 0.00277

Gnomad4 OTH exome AF: 0.00316

GnomAD4 genome AF: 0.00345 AC: 526 AN: 152342 Hom.: 4 Cov.: 32 AF XY: 0.00400 AC XY: 298 AN XY: 74484

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00662

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.0187

Gnomad4 NFE AF: 0.00363

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00327 Hom.: 0

Bravo AF: 0.00196

ESP6500AA AF: 0.000255 AC: 1

ESP6500EA AF: 0.00329 AC: 26

ExAC AF: 0.00404 AC: 474

Asia WGS AF: 0.00491 AC: 17 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Sep 01, 2022

LRFN2: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	0.84
Dann	Benign	0.89
DEOGEN2	Uncertain	0.47	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.44	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.064
Sift	Benign	0.20	T
Sift4G	Benign	0.085	T
Polyphen		0.0	B
Vest4		0.049
MVP		0.38
MPC		0.39
ClinPred		0.0018	T
GERP RS		-1.3
Varity_R		0.031
gMVP		0.19

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

Other links and lift over

dbSNP: rs200804161; hg19: chr6-40360265; COSMIC: COSV100599113;