rs61745812

Variant names:

• chr19-45494188-G-T
• rs61745812
• NM_005619.5:c.792C>A

Your query was ambiguous. Multiple possible variants found:

• chr19-45494188-G-T
• chr19-45494188-G-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.792C>A​(p.Phe264Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00129 in 1,604,630 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0065 (11 hom., cov: 32)
  • Exomes 𝑓: 0.00075 (14 hom.)
• Consequence: RTN2 NM_005619.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.21
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023634732).
• BP6: Variant 19-45494188-G-T is Benign according to our data. Variant chr19-45494188-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 380937.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 = 0.0065 (990/152272) while in subpopulation AFR AF = 0.0215 (892/41552). AF 95% confidence interval is 0.0203. There are 11 homozygotes in GnomAd4. There are 475 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 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.792C>A	p.Phe264Leu	missense	Exon 4 of 11	NP_005610.1	O75298-1
	RTN2	NM_206900.3		c.792C>A	p.Phe264Leu	missense	Exon 4 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.792C>A	p.Phe264Leu	missense	Exon 4 of 11	ENSP00000245923.3	O75298-1
	RTN2	ENST00000344680.8	TSL:1	c.792C>A	p.Phe264Leu	missense	Exon 4 of 10	ENSP00000345127.3	O75298-2
	RTN2	ENST00000591286.5	TSL:1	n.792C>A		non_coding_transcript_exon	Exon 4 of 10	ENSP00000467863.1	Q96CG9

Frequencies

GnomAD3 genomes AF: 0.00648 AC: 986 AN: 152154 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.0214

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00478

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00621

GnomAD2 exomes AF: 0.00167 AC: 407 AN: 243250 AF XY: 0.00117

Gnomad AFR exome AF: 0.0214

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000549

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000443

Gnomad OTH exome AF: 0.00165

GnomAD4 exome AF: 0.000746 AC: 1083 AN: 1452358 Hom.: 14 Cov.: 31 AF XY: 0.000642 AC XY: 464 AN XY: 722744

African (AFR) AF: 0.0247 AC: 828 AN: 33476

American (AMR) AF: 0.00179 AC: 80 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44038

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.0000369 AC: 41 AN: 1111924

Other (OTH) AF: 0.00199 AC: 120 AN: 60342

GnomAD4 genome AF: 0.00650 AC: 990 AN: 152272 Hom.: 11 Cov.: 32 AF XY: 0.00638 AC XY: 475 AN XY: 74450

African (AFR) AF: 0.0215 AC: 892 AN: 41552

American (AMR) AF: 0.00477 AC: 73 AN: 15296

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68002

Other (OTH) AF: 0.00615 AC: 13 AN: 2114

Alfa AF: 0.00244 Hom.: 2

Bravo AF: 0.00796

ESP6500AA AF: 0.0188 AC: 83

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00198 AC: 241

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		2.2
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.020	N
REVEL	Benign	0.027
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.41	T
Polyphen		0.028	B
Vest4		0.088
MutPred		0.28		Gain of disorder (P = 0.062)
MVP		0.082
MPC		0.34
ClinPred		0.0086	T
GERP RS		3.5
Varity_R		0.061
gMVP		0.15
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs61745812; hg19: chr19-45997446;