rs139232850

Variant names:

• chr19-45494641-G-C
• rs139232850
• NM_005619.5:c.444C>G

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.444C>G​(p.Gly148Gly) variant causes a synonymous change. The variant allele was found at a frequency of 0.00641 in 1,613,916 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0055 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0065 (44 hom.)
• Consequence: RTN2 NM_005619.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.64
• Publications: 4 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 (BayesDel_noAF=-0.47).
• BP6: Variant 19-45494641-G-C is Benign according to our data. Variant chr19-45494641-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 240194.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00555 (845/152326) while in subpopulation NFE AF = 0.00776 (528/68022). AF 95% confidence interval is 0.00721. There are 5 homozygotes in GnomAd4. There are 369 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AD,AR 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.444C>G	p.Gly148Gly	synonymous	Exon 3 of 11	NP_005610.1	O75298-1
	RTN2	NM_206900.3		c.444C>G	p.Gly148Gly	synonymous	Exon 3 of 10	NP_996783.1	O75298-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTN2	ENST00000245923.9	TSL:1 MANE Select	c.444C>G	p.Gly148Gly	synonymous	Exon 3 of 11	ENSP00000245923.3	O75298-1
	RTN2	ENST00000344680.8	TSL:1	c.444C>G	p.Gly148Gly	synonymous	Exon 3 of 10	ENSP00000345127.3	O75298-2
	RTN2	ENST00000591286.5	TSL:1	n.444C>G		non_coding_transcript_exon	Exon 3 of 10	ENSP00000467863.1	Q96CG9

Frequencies

GnomAD3 genomes AF: 0.00556 AC: 846 AN: 152208 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00355

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00458

Gnomad ASJ AF: 0.0176

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00776

Gnomad OTH AF: 0.00764

GnomAD2 exomes AF: 0.00530 AC: 1330 AN: 250854 AF XY: 0.00525

Gnomad AFR exome AF: 0.00284

Gnomad AMR exome AF: 0.00330

Gnomad ASJ exome AF: 0.0167

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00122

Gnomad NFE exome AF: 0.00764

Gnomad OTH exome AF: 0.00473

GnomAD4 exome AF: 0.00650 AC: 9501 AN: 1461590 Hom.: 44 Cov.: 32 AF XY: 0.00638 AC XY: 4639 AN XY: 727090

African (AFR) AF: 0.00272 AC: 91 AN: 33480

American (AMR) AF: 0.00335 AC: 150 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0178 AC: 465 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00290 AC: 250 AN: 86258

European-Finnish (FIN) AF: 0.00151 AC: 80 AN: 53124

Middle Eastern (MID) AF: 0.0107 AC: 62 AN: 5768

European-Non Finnish (NFE) AF: 0.00714 AC: 7938 AN: 1112010

Other (OTH) AF: 0.00767 AC: 463 AN: 60390

GnomAD4 genome AF: 0.00555 AC: 845 AN: 152326 Hom.: 5 Cov.: 32 AF XY: 0.00495 AC XY: 369 AN XY: 74500

African (AFR) AF: 0.00356 AC: 148 AN: 41574

American (AMR) AF: 0.00457 AC: 70 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0176 AC: 61 AN: 3472

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

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4828

European-Finnish (FIN) AF: 0.000659 AC: 7 AN: 10624

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00776 AC: 528 AN: 68022

Other (OTH) AF: 0.00709 AC: 15 AN: 2116

Alfa AF: 0.00834 Hom.: 5

Bravo AF: 0.00571

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00992

EpiControl AF: 0.00931

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	11
DANN	Benign	0.75
PhyloP100		3.6
Mutation Taster		=299/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs139232850; hg19: chr19-45997899; COSMIC: COSV99839353; COSMIC: COSV99839353;