19-45488378-G-C

Variant names:

• chr19-45488378-G-C
• rs1603
• NM_005619.5:c.1497+93C>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_005619.5(RTN2):​c.1497+93C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.22 in 1,361,936 control chromosomes in the GnomAD database, including 34,918 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (3758 hom., cov: 32)
  • Exomes 𝑓: 0.22 (31160 hom.)
• Consequence: RTN2 NM_005619.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0710
• Publications: 13 publications found

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]

RTN2 Gene-Disease associations (from GenCC):

• hereditary spastic paraplegia 12

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• neuronopathy, distal hereditary motor, autosomal recessive 11, with spasticity

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant 19-45488378-G-C is Benign according to our data. Variant chr19-45488378-G-C is described in ClinVar as Benign. ClinVar VariationId is 670893.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.266 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005619.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTN2	NM_005619.5	MANE Select	c.1497+93C>G		intron	N/A	NP_005610.1
	RTN2	NM_206900.3		c.1278+93C>G		intron	N/A	NP_996783.1
	RTN2	NM_206901.3		c.477+93C>G		intron	N/A	NP_996784.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTN2	ENST00000245923.9	TSL:1 MANE Select	c.1497+93C>G		intron	N/A	ENSP00000245923.3
	RTN2	ENST00000344680.8	TSL:1	c.1278+93C>G		intron	N/A	ENSP00000345127.3
	RTN2	ENST00000430715.6	TSL:1	c.477+93C>G		intron	N/A	ENSP00000398178.1

Frequencies

GnomAD3 genomes AF: 0.217 AC: 32938 AN: 152046 Hom.: 3758 Cov.: 32

Gnomad AFR AF: 0.171

Gnomad AMI AF: 0.414

Gnomad AMR AF: 0.222

Gnomad ASJ AF: 0.201

Gnomad EAS AF: 0.278

Gnomad SAS AF: 0.117

Gnomad FIN AF: 0.356

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.223

Gnomad OTH AF: 0.189

GnomAD4 exome AF: 0.221 AC: 267135 AN: 1209772 Hom.: 31160 AF XY: 0.217 AC XY: 131358 AN XY: 604332

African (AFR) AF: 0.168 AC: 4700 AN: 27896

American (AMR) AF: 0.180 AC: 6751 AN: 37560

Ashkenazi Jewish (ASJ) AF: 0.197 AC: 4070 AN: 20704

East Asian (EAS) AF: 0.294 AC: 11233 AN: 38268

South Asian (SAS) AF: 0.115 AC: 8288 AN: 71808

European-Finnish (FIN) AF: 0.348 AC: 17427 AN: 50104

Middle Eastern (MID) AF: 0.0979 AC: 433 AN: 4424

European-Non Finnish (NFE) AF: 0.224 AC: 203404 AN: 907582

Other (OTH) AF: 0.211 AC: 10829 AN: 51426

GnomAD4 genome AF: 0.217 AC: 32961 AN: 152164 Hom.: 3758 Cov.: 32 AF XY: 0.221 AC XY: 16419 AN XY: 74378

African (AFR) AF: 0.171 AC: 7111 AN: 41522

American (AMR) AF: 0.221 AC: 3379 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.201 AC: 697 AN: 3472

East Asian (EAS) AF: 0.278 AC: 1440 AN: 5174

South Asian (SAS) AF: 0.118 AC: 568 AN: 4826

European-Finnish (FIN) AF: 0.356 AC: 3762 AN: 10570

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.223 AC: 15195 AN: 68000

Other (OTH) AF: 0.191 AC: 404 AN: 2112

Alfa AF: 0.119 Hom.: 204

Bravo AF: 0.207

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	1.6
DANN	Benign	0.81
PhyloP100		-0.071
PromoterAI		0.0043	Neutral
Mutation Taster		=99/1	polymorphism (auto)

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: rs1603; hg19: chr19-45991636; COSMIC: COSV55594272; COSMIC: COSV55594272;