6-40392464-G-C

Variant names:

• chr6-40392464-G-C
• rs775968133
• NM_020737.3:c.1849C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020737.3(LRFN2):​c.1849C>G​(p.Arg617Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000212 in 1,415,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: LRFN2 NM_020737.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.30

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17557433).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRFN2	NM_020737.3	c.1849C>G	p.Arg617Gly	missense_variant	Exon 3 of 3	ENST00000338305.7	NP_065788.1
LRFN2	XM_011514762.3	c.1849C>G	p.Arg617Gly	missense_variant	Exon 3 of 3		XP_011513064.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRFN2	ENST00000338305.7	c.1849C>G	p.Arg617Gly	missense_variant	Exon 3 of 3	1	NM_020737.3	ENSP00000345985.6
LRFN2	ENST00000700335.1	c.1849C>G	p.Arg617Gly	missense_variant	Exon 4 of 4			ENSP00000514953.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000603 AC: 1 AN: 165794 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 90758

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000155

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000212 AC: 3 AN: 1415986 Hom.: 0 Cov.: 34 AF XY: 0.00000285 AC XY: 2 AN XY: 700832

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000276

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000864 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 12, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1849C>G (p.R617G) alteration is located in exon 3 (coding exon 2) of the LRFN2 gene. This alteration results from a C to G substitution at nucleotide position 1849, causing the arginine (R) at amino acid position 617 to be replaced by a glycine (G). 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	0.083
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	16
DANN	Benign	0.86
DEOGEN2	Benign	0.042	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.45
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.060
Sift	Benign	0.065	T
Sift4G	Benign	0.38	T
Polyphen		0.18	B
Vest4		0.28
MutPred		0.28		Gain of loop (P = 0.0079);
MVP		0.67
MPC		0.43
ClinPred		0.071	T
GERP RS		3.8
Varity_R		0.12
gMVP		0.077

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: rs775968133; hg19: chr6-40360203;