chr6-87514303-C-T

Variant names:

• chr6-87514303-C-T
• rs565043397
• NM_020320.5:c.*110G>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_001350505.2(RARS2):​c.1728G>A​(p.Glu576Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00094 in 674,710 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00086 (0 hom., cov: 29)
  • Exomes 𝑓: 0.00096 (0 hom.)
• Consequence: RARS2 NM_001350505.2 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.132
• Publications: 0 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BP6: Variant 6-87514303-C-T is Benign according to our data. Variant chr6-87514303-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3770781.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.132 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001350505.2. 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.*110G>A		3_prime_UTR	Exon 20 of 20	NP_064716.2	Q5T160
	RARS2	NM_001350505.2		c.1728G>A	p.Glu576Glu	synonymous	Exon 21 of 21	NP_001337434.1	A0A8I5KWC6
	RARS2	NM_001350506.2		c.1203G>A	p.Glu401Glu	synonymous	Exon 21 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.*110G>A		3_prime_UTR	Exon 20 of 20	ENSP00000358549.5	Q5T160
	RARS2	ENST00000691725.1		c.1728G>A	p.Glu576Glu	synonymous	Exon 21 of 21	ENSP00000509453.1	A0A8I5KWC6
	RARS2	ENST00000693431.1		c.1203G>A	p.Glu401Glu	synonymous	Exon 21 of 21	ENSP00000509147.1	A0A8I5KPZ0

Frequencies

GnomAD3 genomes AF: 0.000861 AC: 120 AN: 139326 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.000267

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000376

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: 0.00162

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000960 AC: 514 AN: 535286 Hom.: 0 AF XY: 0.000904 AC XY: 260 AN XY: 287534

African (AFR) AF: 0.0000796 AC: 1 AN: 12562

American (AMR) AF: 0.000221 AC: 5 AN: 22606

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15504

East Asian (EAS) AF: 0.00 AC: 0 AN: 24738

South Asian (SAS) AF: 0.0000733 AC: 4 AN: 54534

European-Finnish (FIN) AF: 0.000148 AC: 5 AN: 33778

Middle Eastern (MID) AF: 0.000507 AC: 1 AN: 1972

European-Non Finnish (NFE) AF: 0.00138 AC: 474 AN: 343850

Other (OTH) AF: 0.000932 AC: 24 AN: 25742

GnomAD4 genome AF: 0.000861 AC: 120 AN: 139424 Hom.: 0 Cov.: 29 AF XY: 0.000744 AC XY: 50 AN XY: 67178

African (AFR) AF: 0.000266 AC: 10 AN: 37620

American (AMR) AF: 0.000375 AC: 5 AN: 13316

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3368

East Asian (EAS) AF: 0.00 AC: 0 AN: 4878

South Asian (SAS) AF: 0.00 AC: 0 AN: 4266

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8088

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 266

European-Non Finnish (NFE) AF: 0.00162 AC: 105 AN: 64864

Other (OTH) AF: 0.00 AC: 0 AN: 1872

Alfa AF: 0.00126 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	4.0
DANN	Benign	0.48
PhyloP100		-0.13

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs565043397; hg19: chr6-88224021;