rs73496064

Variant names:

• chr6-87564188-T-A
• rs73496064
• NM_020320.5:c.155A>T

Your query was ambiguous. Multiple possible variants found:

• chr6-87564188-T-A
• chr6-87564188-T-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001350505.2(RARS2):​c.155A>T​(p.Lys52Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00125 in 1,613,864 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K52R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0062 (10 hom., cov: 33)
  • Exomes 𝑓: 0.00073 (11 hom.)
• Consequence: RARS2 NM_001350505.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.776
• Publications: 4 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: Orphanet, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, PanelApp Australia
• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0039069653).
• BP6: Variant 6-87564188-T-A is Benign according to our data. Variant chr6-87564188-T-A is described in ClinVar as Benign. ClinVar VariationId is 130094.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 = 0.00619 (943/152322) while in subpopulation AFR AF = 0.0207 (859/41564). AF 95% confidence interval is 0.0195. There are 10 homozygotes in GnomAd4. There are 428 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 AR,AD gene

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.155A>T	p.Lys52Ile	missense	Exon 3 of 20	NP_064716.2
	RARS2	NM_001350505.2		c.155A>T	p.Lys52Ile	missense	Exon 3 of 21	NP_001337434.1
	RARS2	NM_001350506.2		c.-371A>T		5_prime_UTR	Exon 3 of 21	NP_001337435.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RARS2	ENST00000369536.10	TSL:1 MANE Select	c.155A>T	p.Lys52Ile	missense	Exon 3 of 20	ENSP00000358549.5
	RARS2	ENST00000687437.1		c.155A>T	p.Lys52Ile	missense	Exon 3 of 21	ENSP00000508968.1
	RARS2	ENST00000691725.1		c.155A>T	p.Lys52Ile	missense	Exon 3 of 21	ENSP00000509453.1

Frequencies

GnomAD3 genomes AF: 0.00618 AC: 940 AN: 152204 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.0207

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00621

GnomAD2 exomes AF: 0.00172 AC: 431 AN: 251264 AF XY: 0.00137

Gnomad AFR exome AF: 0.0213

Gnomad AMR exome AF: 0.00171

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.000733 AC: 1072 AN: 1461542 Hom.: 11 Cov.: 31 AF XY: 0.000633 AC XY: 460 AN XY: 727104

African (AFR) AF: 0.0236 AC: 791 AN: 33466

American (AMR) AF: 0.00190 AC: 85 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53356

Middle Eastern (MID) AF: 0.00312 AC: 18 AN: 5768

European-Non Finnish (NFE) AF: 0.0000378 AC: 42 AN: 1111786

Other (OTH) AF: 0.00204 AC: 123 AN: 60380

GnomAD4 genome AF: 0.00619 AC: 943 AN: 152322 Hom.: 10 Cov.: 33 AF XY: 0.00575 AC XY: 428 AN XY: 74484

African (AFR) AF: 0.0207 AC: 859 AN: 41564

American (AMR) AF: 0.00373 AC: 57 AN: 15298

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68020

Other (OTH) AF: 0.00614 AC: 13 AN: 2116

Alfa AF: 0.000372 Hom.: 0

Bravo AF: 0.00711

ESP6500AA AF: 0.0168 AC: 74

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00200 AC: 243

Asia WGS AF: 0.00144 AC: 6 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000296

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Pontocerebellar hypoplasia type 6 (3)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	18
DANN	Benign	0.82
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.058	N
LIST_S2	Benign	0.35	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.78
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.15
Sift	Benign	0.17	T
Sift4G	Benign	0.20	T
Polyphen		0.0	B
Vest4		0.28
MVP		0.69
MPC		0.19
ClinPred		0.0026	T
GERP RS		0.19
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.072
gMVP		0.50
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs73496064; hg19: chr6-88273906;