6-40392096-C-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_020737.3(LRFN2):c.2217G>T(p.Pro739=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.003 in 1,613,706 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (26 hom.)
• Consequence: LRFN2 NM_020737.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.862

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 6-40392096-C-A is Benign according to our data. Variant chr6-40392096-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 728592.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.862 with no splicing effect.
• BS2: High AC in GnomAd at 584 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRFN2	NM_020737.3	c.2217G>T	p.Pro739=	synonymous_variant	3/3	ENST00000338305.7
LRFN2	XM_011514762.3	c.2217G>T	p.Pro739=	synonymous_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRFN2	ENST00000338305.7	c.2217G>T	p.Pro739=	synonymous_variant	3/3	1	NM_020737.3	P1

Frequencies

GnomAD3 genomes AF: 0.00384 AC: 584 AN: 152200 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00406

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.0272

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00297

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00407 AC: 1009 AN: 247744 Hom.: 14 AF XY: 0.00420 AC XY: 565 AN XY: 134470

Gnomad AFR exome AF: 0.000318

Gnomad AMR exome AF: 0.00186

Gnomad ASJ exome AF: 0.00181

Gnomad EAS exome AF: 0.0000548

Gnomad SAS exome AF: 0.000721

Gnomad FIN exome AF: 0.0258

Gnomad NFE exome AF: 0.00278

Gnomad OTH exome AF: 0.00562

GnomAD4 exome AF: 0.00291 AC: 4259 AN: 1461388 Hom.: 26 Cov.: 34 AF XY: 0.00289 AC XY: 2100 AN XY: 726952

Gnomad4 AFR exome AF: 0.000627

Gnomad4 AMR exome AF: 0.00184

Gnomad4 ASJ exome AF: 0.00207

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000998

Gnomad4 FIN exome AF: 0.0257

Gnomad4 NFE exome AF: 0.00215

Gnomad4 OTH exome AF: 0.00315

GnomAD4 genome AF: 0.00383 AC: 583 AN: 152318 Hom.: 5 Cov.: 32 AF XY: 0.00514 AC XY: 383 AN XY: 74474

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.00405

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.0272

Gnomad4 NFE AF: 0.00297

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00189 Hom.: 0

Bravo AF: 0.00175

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00300

EpiControl AF: 0.00344

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2022	LRFN2: BP4, BP7 -
Benign, criteria provided, single submitter	clinical testing	Invitae	May 15, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	0.027
Dann	Benign	0.52

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: rs142012380; hg19: chr6-40359835; COSMIC: COSV57827355;