11-57476480-C-T

Variant names:

• chr11-57476480-C-T
• rs746129231
• NM_178570.3:c.832C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_178570.3(RTN4RL2):​c.832C>T​(p.Arg278Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000132 in 1,512,018 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R278S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: RTN4RL2 NM_178570.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.358
• Publications: 0 publications found

Genes affected

RTN4RL2 (HGNC:23053): (reticulon 4 receptor like 2) Enables signaling receptor activity. Predicted to be involved in cell surface receptor signaling pathway; corpus callosum development; and negative regulation of neuron projection development. Located in cell surface. Is anchored component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000255301 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.42036444).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_178570.3. 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
	RTN4RL2	NM_178570.3	MANE Select	c.832C>T	p.Arg278Cys	missense	Exon 3 of 3	NP_848665.1	Q86UN3-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTN4RL2	ENST00000335099.8	TSL:1 MANE Select	c.832C>T	p.Arg278Cys	missense	Exon 3 of 3	ENSP00000335397.3	Q86UN3-1
	ENSG00000255301	ENST00000528885.1	TSL:2	n.*13G>A		downstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151778 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

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

GnomAD4 exome AF: 7.35e-7 AC: 1 AN: 1360240 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 672732

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 28190

American (AMR) AF: 0.00 AC: 0 AN: 32168

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23078

East Asian (EAS) AF: 0.00 AC: 0 AN: 33154

South Asian (SAS) AF: 0.00 AC: 0 AN: 75520

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34506

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5510

European-Non Finnish (NFE) AF: 9.33e-7 AC: 1 AN: 1071628

Other (OTH) AF: 0.00 AC: 0 AN: 56486

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151778 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74110

African (AFR) AF: 0.0000242 AC: 1 AN: 41366

American (AMR) AF: 0.00 AC: 0 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10508

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67884

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.14
FATHMM_MKL	Benign	0.33	N
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.61	D
MetaRNN	Benign	0.42	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		-0.36
PrimateAI	Pathogenic	0.96	D
PROVEAN	Pathogenic	-5.8	D
REVEL	Benign	0.16
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.99	D
Vest4		0.35
MutPred		0.44		Loss of MoRF binding (P = 0.0114)
MVP		0.32
MPC		2.4
ClinPred		0.98	D
GERP RS		3.4
Varity_R		0.44
gMVP		0.77
Mutation Taster		=90/10	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: rs746129231; hg19: chr11-57243953;