19-45489419-C-T

Variant names:

• chr19-45489419-C-T
• rs143937661
• NM_005619.5:c.1168G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005619.5(RTN2):​c.1168G>A​(p.Gly390Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00275 in 1,606,818 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G390G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0024 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0028 (14 hom.)
• Consequence: RTN2 NM_005619.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.241
• Publications: 8 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]

PPM1N (HGNC:26845): (protein phosphatase, Mg2+/Mn2+ dependent 1N (putative)) Predicted to enable metal ion binding activity and protein serine/threonine phosphatase activity. Predicted to be involved in negative regulation of I-kappaB kinase/NF-kappaB signaling and positive regulation of canonical Wnt signaling pathway. Predicted to be active in cytosol and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008215159).
• BP6: Variant 19-45489419-C-T is Benign according to our data. Variant chr19-45489419-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 329549.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00236 (359/152080) while in subpopulation SAS AF = 0.00707 (34/4810). AF 95% confidence interval is 0.0052. There are 0 homozygotes in GnomAd4. There are 178 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 14 AR,AD gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTN2	NM_005619.5	MANE Select	c.1168G>A	p.Gly390Ser	missense	Exon 6 of 11	NP_005610.1	O75298-1
	RTN2	NM_206900.3		c.949G>A	p.Gly317Ser	missense	Exon 5 of 10	NP_996783.1	O75298-2
	RTN2	NM_206901.3		c.148G>A	p.Gly50Ser	missense	Exon 2 of 7	NP_996784.1	O75298-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTN2	ENST00000245923.9	TSL:1 MANE Select	c.1168G>A	p.Gly390Ser	missense	Exon 6 of 11	ENSP00000245923.3	O75298-1
	RTN2	ENST00000344680.8	TSL:1	c.949G>A	p.Gly317Ser	missense	Exon 5 of 10	ENSP00000345127.3	O75298-2
	RTN2	ENST00000430715.6	TSL:1	c.148G>A	p.Gly50Ser	missense	Exon 2 of 7	ENSP00000398178.1	O75298-3

Frequencies

GnomAD3 genomes AF: 0.00236 AC: 359 AN: 151962 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000581

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00498

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00706

Gnomad FIN AF: 0.000566

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00306

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00280 AC: 665 AN: 237610 AF XY: 0.00310

Gnomad AFR exome AF: 0.000462

Gnomad AMR exome AF: 0.00451

Gnomad ASJ exome AF: 0.000613

Gnomad EAS exome AF: 0.000114

Gnomad FIN exome AF: 0.000650

Gnomad NFE exome AF: 0.00265

Gnomad OTH exome AF: 0.00240

GnomAD4 exome AF: 0.00279 AC: 4064 AN: 1454738 Hom.: 14 Cov.: 32 AF XY: 0.00304 AC XY: 2196 AN XY: 722964

African (AFR) AF: 0.000360 AC: 12 AN: 33374

American (AMR) AF: 0.00445 AC: 194 AN: 43626

Ashkenazi Jewish (ASJ) AF: 0.000655 AC: 17 AN: 25968

East Asian (EAS) AF: 0.000102 AC: 4 AN: 39380

South Asian (SAS) AF: 0.00715 AC: 605 AN: 84660

European-Finnish (FIN) AF: 0.000662 AC: 35 AN: 52864

Middle Eastern (MID) AF: 0.00417 AC: 24 AN: 5752

European-Non Finnish (NFE) AF: 0.00274 AC: 3041 AN: 1108984

Other (OTH) AF: 0.00220 AC: 132 AN: 60130

GnomAD4 genome AF: 0.00236 AC: 359 AN: 152080 Hom.: 0 Cov.: 30 AF XY: 0.00239 AC XY: 178 AN XY: 74344

African (AFR) AF: 0.000579 AC: 24 AN: 41448

American (AMR) AF: 0.00498 AC: 76 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5170

South Asian (SAS) AF: 0.00707 AC: 34 AN: 4810

European-Finnish (FIN) AF: 0.000566 AC: 6 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00306 AC: 208 AN: 67998

Other (OTH) AF: 0.00379 AC: 8 AN: 2110

Alfa AF: 0.00248 Hom.: 5

Bravo AF: 0.00244

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.00326 AC: 28

ExAC AF: 0.00278 AC: 337

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	not specified (1)
-	-	1	Spastic paraplegia (1)
-	-	1	Spastic paraplegia, autosomal dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.046	N
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.0082	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L
PhyloP100		0.24
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	0.63	N
REVEL	Benign	0.040
Sift	Benign	0.39	T
Sift4G	Benign	0.44	T
Polyphen		0.97	D
Vest4		0.40
MVP		0.13
MPC		0.36
ClinPred		0.0063	T
GERP RS		2.3
Varity_R		0.061
gMVP		0.56
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs143937661; hg19: chr19-45992677;