rs148270789

Variant names:

• chr19-45488916-G-A
• rs148270789
• NM_005619.5:c.1312C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_005619.5(RTN2):​c.1312C>T​(p.Arg438Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000107 in 1,610,046 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R438H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00042 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000075 (0 hom.)
• Consequence: RTN2 NM_005619.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.136
• Publications: 0 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.019652128).
• BP6: Variant 19-45488916-G-A is Benign according to our data. Variant chr19-45488916-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 448172.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00042 (64/152204) while in subpopulation AFR AF = 0.0015 (62/41456). AF 95% confidence interval is 0.0012. There are 0 homozygotes in GnomAd4. There are 27 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.1312C>T	p.Arg438Cys	missense	Exon 7 of 11	NP_005610.1	O75298-1
	RTN2	NM_206900.3		c.1093C>T	p.Arg365Cys	missense	Exon 6 of 10	NP_996783.1	O75298-2
	RTN2	NM_206901.3		c.292C>T	p.Arg98Cys	missense	Exon 3 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.1312C>T	p.Arg438Cys	missense	Exon 7 of 11	ENSP00000245923.3	O75298-1
	RTN2	ENST00000344680.8	TSL:1	c.1093C>T	p.Arg365Cys	missense	Exon 6 of 10	ENSP00000345127.3	O75298-2
	RTN2	ENST00000430715.6	TSL:1	c.292C>T	p.Arg98Cys	missense	Exon 3 of 7	ENSP00000398178.1	O75298-3

Frequencies

GnomAD3 genomes AF: 0.000420 AC: 64 AN: 152204 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000162 AC: 39 AN: 241134 AF XY: 0.000123

Gnomad AFR exome AF: 0.00208

Gnomad AMR exome AF: 0.0000596

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000112

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000183

Gnomad OTH exome AF: 0.000169

GnomAD4 exome AF: 0.0000748 AC: 109 AN: 1457842 Hom.: 0 Cov.: 33 AF XY: 0.0000676 AC XY: 49 AN XY: 724776

African (AFR) AF: 0.00206 AC: 69 AN: 33424

American (AMR) AF: 0.0000454 AC: 2 AN: 44034

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25994

East Asian (EAS) AF: 0.000455 AC: 18 AN: 39546

South Asian (SAS) AF: 0.00 AC: 0 AN: 85270

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53042

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.0000153 AC: 17 AN: 1110526

Other (OTH) AF: 0.0000498 AC: 3 AN: 60244

GnomAD4 genome AF: 0.000420 AC: 64 AN: 152204 Hom.: 0 Cov.: 32 AF XY: 0.000363 AC XY: 27 AN XY: 74364

African (AFR) AF: 0.00150 AC: 62 AN: 41456

American (AMR) AF: 0.0000654 AC: 1 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000143 Hom.: 0

Bravo AF: 0.000563

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000214 AC: 26

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)
-	-	1	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.038
Eigen_PC	Benign	-0.085
FATHMM_MKL	Benign	0.063	N
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.020	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L
PhyloP100		-0.14
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.14
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.014	D
Polyphen		0.99	D
Vest4		0.19
MVP		0.082
MPC		0.39
ClinPred		0.023	T
GERP RS		2.2
PromoterAI		0.050	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.54
Mutation Taster		=88/12	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: rs148270789; hg19: chr19-45992174;