rs527298509

Variant names:

• chr19-45485438-G-A
• rs527298509
• NM_005619.5:c.*270C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-45485438-G-A
• chr19-45485438-G-C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_005619.5(RTN2):​c.*270C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000239 in 502,474 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000057 (0 hom.)
• Consequence: RTN2 NM_005619.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.166
• 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]

RTN2 Gene-Disease associations (from GenCC):

• hereditary spastic paraplegia 12

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• neuronopathy, distal hereditary motor, autosomal recessive 11, with spasticity

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000656 (10/152384) while in subpopulation EAS AF = 0.00193 (10/5184). AF 95% confidence interval is 0.00105. There are 0 homozygotes in GnomAd4. There are 5 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.*270C>T		3_prime_UTR	Exon 11 of 11	NP_005610.1	O75298-1
	RTN2	NM_206900.3		c.*270C>T		3_prime_UTR	Exon 10 of 10	NP_996783.1	O75298-2
	RTN2	NM_206901.3		c.*270C>T		3_prime_UTR	Exon 7 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.*270C>T		3_prime_UTR	Exon 11 of 11	ENSP00000245923.3	O75298-1
	RTN2	ENST00000344680.8	TSL:1	c.*270C>T		3_prime_UTR	Exon 10 of 10	ENSP00000345127.3	O75298-2
	RTN2	ENST00000430715.6	TSL:1	c.*270C>T		3_prime_UTR	Exon 7 of 7	ENSP00000398178.1	O75298-3

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152266 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00192

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: 0.00000571 AC: 2 AN: 350090 Hom.: 0 Cov.: 0 AF XY: 0.00000546 AC XY: 1 AN XY: 183204

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 10606

American (AMR) AF: 0.00 AC: 0 AN: 14890

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11196

East Asian (EAS) AF: 0.0000804 AC: 2 AN: 24866

South Asian (SAS) AF: 0.00 AC: 0 AN: 34788

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22074

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1560

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 209352

Other (OTH) AF: 0.00 AC: 0 AN: 20758

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000656 AC: 10 AN: 152384 Hom.: 0 Cov.: 32 AF XY: 0.0000671 AC XY: 5 AN XY: 74524

African (AFR) AF: 0.00 AC: 0 AN: 41600

American (AMR) AF: 0.00 AC: 0 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00193 AC: 10 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000529

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary spastic paraplegia 12 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	15
DANN	Benign	0.89
PhyloP100		0.17

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: rs527298509; hg19: chr19-45988696;