chr6-40392464-G-A

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_020737.3(LRFN2):​c.1849C>T​(p.Arg617Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000159 in 1,568,240 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. R617G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: LRFN2 NM_020737.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.30
• Publications: 1 publications found

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

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2575294).
• BS2: High AC in GnomAd4 at 6 AD gene.

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.1849C>T	p.Arg617Cys	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.1849C>T	p.Arg617Cys	missense	Exon 3 of 3	ENSP00000345985.6	Q9ULH4
	LRFN2	ENST00000700335.1		c.1849C>T	p.Arg617Cys	missense	Exon 4 of 4	ENSP00000514953.1	A0A8V8TQ63

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152254 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000302 AC: 5 AN: 165794 AF XY: 0.0000220

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000375

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000464

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.0000134 AC: 19 AN: 1415986 Hom.: 0 Cov.: 34 AF XY: 0.00000999 AC XY: 7 AN XY: 700832

African (AFR) AF: 0.00 AC: 0 AN: 32226

American (AMR) AF: 0.0000263 AC: 1 AN: 37964

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25390

East Asian (EAS) AF: 0.00 AC: 0 AN: 36784

South Asian (SAS) AF: 0.00 AC: 0 AN: 82012

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48430

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5690

European-Non Finnish (NFE) AF: 0.0000156 AC: 17 AN: 1088886

Other (OTH) AF: 0.0000171 AC: 1 AN: 58604

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152254 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74382

African (AFR) AF: 0.0000241 AC: 1 AN: 41472

American (AMR) AF: 0.000262 AC: 4 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000569 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000346 AC: 4

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.065	T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N
PhyloP100		5.3
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.87	N
REVEL	Benign	0.16
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.053	T
Polyphen		0.97	D
Vest4		0.32
MutPred		0.34		Loss of helix (P = 0.0138)
MVP		0.71
MPC		0.54
ClinPred		0.18	T
GERP RS		3.8
Varity_R		0.12
gMVP		0.062
Mutation Taster		=79/21	polymorphism

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

Other links and lift over

dbSNP: rs775968133; hg19: chr6-40360203; COSMIC: COSV100600065;