11-57460884-C-A

Variant names:

• chr11-57460884-C-A
• rs111949084
• NM_178570.3:c.19C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_178570.3(RTN4RL2):​c.19C>A​(p.Arg7Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000159 in 1,254,658 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. R7C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: RTN4RL2 NM_178570.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.63
• Publications: 1 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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2012276).

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.19C>A	p.Arg7Ser	missense	Exon 1 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.19C>A	p.Arg7Ser	missense	Exon 1 of 3	ENSP00000335397.3	Q86UN3-1
	RTN4RL2	ENST00000395120.2	TSL:1	c.19C>A	p.Arg7Ser	missense	Exon 1 of 3	ENSP00000378552.2	Q86UN3-2
	RTN4RL2	ENST00000533205.5	TSL:3	c.19C>A	p.Arg7Ser	missense	Exon 1 of 3	ENSP00000435606.1	G3V1D7

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000159 AC: 2 AN: 1254658 Hom.: 0 Cov.: 29 AF XY: 0.00000163 AC XY: 1 AN XY: 614928

⚠️ 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: 25726

American (AMR) AF: 0.00 AC: 0 AN: 21512

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21326

East Asian (EAS) AF: 0.00 AC: 0 AN: 27536

South Asian (SAS) AF: 0.00 AC: 0 AN: 61798

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44290

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3678

European-Non Finnish (NFE) AF: 0.00000200 AC: 2 AN: 998622

Other (OTH) AF: 0.00 AC: 0 AN: 50170

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0448430), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.099	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.62	T
M_CAP	Pathogenic	0.93	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.6	L
PhyloP100		1.6
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.62	N
REVEL	Benign	0.043
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.79	T
Polyphen		0.0	B
Vest4		0.15
MutPred		0.44		Loss of methylation at R7 (P = 0.0112)
MVP		0.35
MPC		1.6
ClinPred		0.38	T
GERP RS		3.0
PromoterAI		0.025	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.29
gMVP		0.69
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: rs111949084; hg19: chr11-57228357;