19-45488378-G-T

Variant names:

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

Variant summary

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

The NM_005619.5(RTN2):​c.1497+93C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000033 in 1,211,288 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.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000033 (0 hom.)
• Consequence: RTN2 NM_005619.5 intron
• Clinical Significance: Not reported in ClinVar
• 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: 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 (BayesDel_noAF=-0.28).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RTN2	NM_005619.5	c.1497+93C>A		intron_variant	Intron 9 of 10	ENST00000245923.9	NP_005610.1
RTN2	NM_206900.3	c.1278+93C>A		intron_variant	Intron 8 of 9		NP_996783.1
RTN2	NM_206901.3	c.477+93C>A		intron_variant	Intron 5 of 6		NP_996784.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RTN2	ENST00000245923.9	c.1497+93C>A		intron_variant	Intron 9 of 10	1	NM_005619.5	ENSP00000245923.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000330 AC: 4 AN: 1211288 Hom.: 0 AF XY: 0.00000331 AC XY: 2 AN XY: 605000

⚠️ 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: 27912

American (AMR) AF: 0.00 AC: 0 AN: 37574

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20722

East Asian (EAS) AF: 0.00 AC: 0 AN: 38284

South Asian (SAS) AF: 0.00 AC: 0 AN: 71832

European-Finnish (FIN) AF: 0.0000199 AC: 1 AN: 50154

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4424

European-Non Finnish (NFE) AF: 0.00000110 AC: 1 AN: 908908

Other (OTH) AF: 0.0000389 AC: 2 AN: 51478

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00448627), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 204

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	1.6
DANN	Benign	0.88
PhyloP100		-0.071
PromoterAI		0.029	Neutral

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;