19-45489419-C-G

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BS1

The NM_005619.5(RTN2):​c.1168G>C​(p.Gly390Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000311 in 1,606,704 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G390S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 30)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RTN2 NM_005619.5 missense
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0000263 (4/151964) while in subpopulation AMR AF = 0.000262 (4/15246). AF 95% confidence interval is 0.0000889. There are 0 homozygotes in GnomAd4. There are 3 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RTN2	NM_005619.5	c.1168G>C	p.Gly390Arg	missense_variant	Exon 6 of 11	ENST00000245923.9	NP_005610.1
RTN2	NM_206900.3	c.949G>C	p.Gly317Arg	missense_variant	Exon 5 of 10		NP_996783.1
RTN2	NM_206901.3	c.148G>C	p.Gly50Arg	missense_variant	Exon 2 of 7		NP_996784.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RTN2	ENST00000245923.9	c.1168G>C	p.Gly390Arg	missense_variant	Exon 6 of 11	1	NM_005619.5	ENSP00000245923.3

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 151964 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1454740 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 722966

African (AFR) AF: 0.00 AC: 0 AN: 33374

American (AMR) AF: 0.00 AC: 0 AN: 43626

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25968

East Asian (EAS) AF: 0.00 AC: 0 AN: 39380

South Asian (SAS) AF: 0.00 AC: 0 AN: 84660

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52864

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108986

Other (OTH) AF: 0.00 AC: 0 AN: 60130

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 151964 Hom.: 0 Cov.: 30 AF XY: 0.0000404 AC XY: 3 AN XY: 74216

African (AFR) AF: 0.00 AC: 0 AN: 41326

American (AMR) AF: 0.000262 AC: 4 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 5

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T;.;T;.
Eigen	Benign	0.0031
Eigen_PC	Benign	-0.073
FATHMM_MKL	Benign	0.088	N
LIST_S2	Uncertain	0.92	D;D;D;D
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.72	D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;.;.;.
PhyloP100		0.24
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.75	N;N;.;N
REVEL	Benign	0.25
Sift	Benign	0.049	D;T;.;T
Sift4G	Benign	0.065	T;T;T;T
Polyphen		1.0	D;.;.;P
Vest4		0.56
MutPred		0.90		Gain of MoRF binding (P = 0.0205);.;.;.;
MVP		0.15
MPC		0.99
ClinPred		0.50	T
GERP RS		2.3
Varity_R		0.32
gMVP		0.76
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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;