19-45485716-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_005619.5(RTN2):c.1630G>A(p.Ala544Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00041 in 1,613,908 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00044 (2 hom.)
• Consequence: RTN2 NM_005619.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 3.32

Genes affected

RTN2 (HGNC:10468): (reticulon 2) This gene belongs to the family of reticulon encoding genes. Reticulons are associated with the endoplasmic reticulum, and are involved in neuroendocrine secretion or in membrane trafficking in neuroendocrine cells. Reticulon proteins also play an important role in the replication of positive-strand RNA (ssRNA) viruses. Mutations at this locus have been associated with autosomal dominant spastic paraplegia-12. [provided by RefSeq, Aug 2020]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05960411).
• BP6: Variant 19-45485716-C-T is Benign according to our data. Variant chr19-45485716-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 653220.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000436 (637/1461626) while in subpopulation MID AF= 0.00052 (3/5764). AF 95% confidence interval is 0.000481. There are 2 homozygotes in gnomad4_exome. There are 327 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RTN2	NM_005619.5	c.1630G>A	p.Ala544Thr	missense_variant	11/11	ENST00000245923.9
RTN2	NM_206900.3	c.1411G>A	p.Ala471Thr	missense_variant	10/10
RTN2	NM_206901.3	c.610G>A	p.Ala204Thr	missense_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RTN2	ENST00000245923.9	c.1630G>A	p.Ala544Thr	missense_variant	11/11	1	NM_005619.5

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152164 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000160 AC: 40 AN: 249938 Hom.: 0 AF XY: 0.000229 AC XY: 31 AN XY: 135230

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000359

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000205

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000436 AC: 637 AN: 1461626 Hom.: 2 Cov.: 31 AF XY: 0.000450 AC XY: 327 AN XY: 727136

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000429

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000516

Gnomad4 OTH exome AF: 0.000331

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152282 Hom.: 0 Cov.: 31 AF XY: 0.000134 AC XY: 10 AN XY: 74446

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000258 Hom.: 0

Bravo AF: 0.000151

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000206 AC: 25

EpiCase AF: 0.000382

EpiControl AF: 0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary spastic paraplegia 12 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 25, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Spastic paraplegia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 10, 2023

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 544 of the RTN2 protein (p.Ala544Thr). This variant is present in population databases (rs201387324, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with RTN2-related conditions. ClinVar contains an entry for this variant (Variation ID: 653220). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 01, 2022

The c.1630G>A (p.A544T) alteration is located in exon 11 (coding exon 11) of the RTN2 gene. This alteration results from a G to A substitution at nucleotide position 1630, causing the alanine (A) at amino acid position 544 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Apr 20, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.29
Cadd	Uncertain	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.076	T;.;T;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.81	T;T;T;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.060	T;T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.69	N;.;.;.
MutationTaster	Benign	0.99	N;N;N;N
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.10	N;N;.;N
REVEL	Benign	0.11
Sift	Pathogenic	0.0	D;T;.;D
Sift4G	Benign	0.12	T;T;T;T
Polyphen		0.99	D;.;.;D
Vest4		0.20
MVP		0.093
MPC		0.27
ClinPred		0.10	T
GERP RS		4.1
Varity_R		0.35
gMVP		0.37

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: rs201387324; hg19: chr19-45988974;