19-45485789-C-G

Variant names:

• chr19-45485789-C-G
• NM_005619.5:c.1557G>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_005619.5(RTN2):​c.1557G>C​(p.Lys519Asn) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,328 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RTN2 NM_005619.5 missense, splice_region
• Scores: Splicing: ADA: 0.9996
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.65

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RTN2	NM_005619.5	c.1557G>C	p.Lys519Asn	missense_variant, splice_region_variant	Exon 11 of 11	ENST00000245923.9	NP_005610.1
RTN2	NM_206900.3	c.1338G>C	p.Lys446Asn	missense_variant, splice_region_variant	Exon 10 of 10		NP_996783.1
RTN2	NM_206901.3	c.537G>C	p.Lys179Asn	missense_variant, splice_region_variant	Exon 7 of 7		NP_996784.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RTN2	ENST00000245923.9	c.1557G>C	p.Lys519Asn	missense_variant, splice_region_variant	Exon 11 of 11	1	NM_005619.5	ENSP00000245923.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461328 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726972

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Benign	-0.032	T
BayesDel_noAF	Benign	-0.28
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D;.;T;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.82	T;T;T;T
MetaRNN	Benign	0.34	T;T;T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Uncertain	2.4	M;.;.;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-4.7	D;D;.;D
REVEL	Benign	0.14
Sift	Uncertain	0.014	D;D;.;D
Sift4G	Uncertain	0.025	D;T;T;D
Polyphen		0.69	P;.;.;D
Vest4		0.38
MutPred		0.48		Loss of ubiquitination at K519 (P = 0.0283);.;.;.;
MVP		0.36
MPC		0.46
ClinPred		0.99	D
GERP RS		3.6
Varity_R		0.42
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.85
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-45989047;