NM_020320.5:c.888G>C

Variant names:

• chr6-87524643-C-G
• rs145189950
• NM_020320.5:c.888G>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_020320.5(RARS2):​c.888G>C​(p.Thr296Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00107 in 1,610,434 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T296T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (2 hom.)
• Consequence: RARS2 NM_020320.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: -0.621
• Publications: 2 publications found

Genes affected

RARS2 (HGNC:21406): (arginyl-tRNA synthetase 2, mitochondrial) This nuclear gene encodes a protein that localizes to the mitochondria, where it catalyzes the transfer of L-arginine to its cognate tRNA, an important step in translation of mitochondrially-encoded proteins. Defects in this gene are a cause of pontocerebellar hypoplasia type 6 (PCH6). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

RARS2 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• pontocerebellar hypoplasia type 6

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P, Laboratory for Molecular Medicine, Ambry Genetics
• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 6-87524643-C-G is Benign according to our data. Variant chr6-87524643-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 138896.
• BP7: Synonymous conserved (PhyloP=-0.621 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020320.5. 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
	RARS2	NM_020320.5	MANE Select	c.888G>C	p.Thr296Thr	synonymous	Exon 11 of 20	NP_064716.2	Q5T160
	RARS2	NM_001350505.2		c.888G>C	p.Thr296Thr	synonymous	Exon 11 of 21	NP_001337434.1	A0A8I5KWC6
	RARS2	NM_001350506.2		c.363G>C	p.Thr121Thr	synonymous	Exon 11 of 21	NP_001337435.1	A0A8I5KPZ0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RARS2	ENST00000369536.10	TSL:1 MANE Select	c.888G>C	p.Thr296Thr	synonymous	Exon 11 of 20	ENSP00000358549.5	Q5T160
	RARS2	ENST00000687437.1		c.888G>C	p.Thr296Thr	synonymous	Exon 11 of 21	ENSP00000508968.1	A0A8I5KP51
	RARS2	ENST00000691725.1		c.888G>C	p.Thr296Thr	synonymous	Exon 11 of 21	ENSP00000509453.1	A0A8I5KWC6

Frequencies

GnomAD3 genomes AF: 0.00119 AC: 181 AN: 152090 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.0173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00142

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00143

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00130 AC: 325 AN: 250892 AF XY: 0.00131

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.0102

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00131

Gnomad NFE exome AF: 0.00149

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.00106 AC: 1546 AN: 1458226 Hom.: 2 Cov.: 30 AF XY: 0.00112 AC XY: 815 AN XY: 725670

African (AFR) AF: 0.0000898 AC: 3 AN: 33420

American (AMR) AF: 0.000157 AC: 7 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0123 AC: 321 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.000429 AC: 37 AN: 86170

European-Finnish (FIN) AF: 0.00119 AC: 63 AN: 53116

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000916 AC: 1016 AN: 1108938

Other (OTH) AF: 0.00164 AC: 99 AN: 60308

GnomAD4 genome AF: 0.00119 AC: 181 AN: 152208 Hom.: 0 Cov.: 32 AF XY: 0.00112 AC XY: 83 AN XY: 74416

African (AFR) AF: 0.000120 AC: 5 AN: 41550

American (AMR) AF: 0.0000654 AC: 1 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0173 AC: 60 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.00142 AC: 15 AN: 10588

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

European-Non Finnish (NFE) AF: 0.00143 AC: 97 AN: 68004

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00208 Hom.: 0

Bravo AF: 0.00105

EpiCase AF: 0.00136

EpiControl AF: 0.00184

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	1	not specified (2)
-	1	1	Pontocerebellar hypoplasia type 6 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.61
DANN	Benign	0.48
PhyloP100		-0.62
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs145189950; hg19: chr6-88234361; COSMIC: COSV65761112;