6-44304512-G-C

Variant names:

• chr6-44304512-G-C
• NM_020745.4:c.1774C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2 PM5 BP4_Moderate

The NM_020745.4(AARS2):​c.1774C>G​(p.Arg592Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. 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. R592W) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: AARS2 NM_020745.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.555

Genes affected

AARS2 (HGNC:21022): (alanyl-tRNA synthetase 2, mitochondrial) The protein encoded by this gene belongs to the class-II aminoacyl-tRNA synthetase family. Aminoacyl-tRNA synthetases play critical roles in mRNA translation by charging tRNAs with their cognate amino acids. The encoded protein is a mitochondrial enzyme that specifically aminoacylates alanyl-tRNA. Mutations in this gene are a cause of combined oxidative phosphorylation deficiency 8. [provided by RefSeq, Dec 2011]

ENSG00000272442 (HGNC:):

TMEM151B (HGNC:21315): (transmembrane protein 151B) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-44304512-G-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.081495166).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AARS2	NM_020745.4	c.1774C>G	p.Arg592Gly	missense_variant	Exon 13 of 22	ENST00000244571.5	NP_065796.2
AARS2	XM_005249245.4	c.1483C>G	p.Arg495Gly	missense_variant	Exon 11 of 20		XP_005249302.1
AARS2	XR_007059282.1	n.1779C>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 13 of 14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AARS2	ENST00000244571.5	c.1774C>G	p.Arg592Gly	missense_variant	Exon 13 of 22	1	NM_020745.4	ENSP00000244571.4
ENSG00000272442	ENST00000505802.1	n.313-2431G>C		intron_variant	Intron 1 of 9	2		ENSP00000424257.1
TMEM151B	ENST00000438774.2	c.577-2431G>C		intron_variant	Intron 2 of 2	3		ENSP00000409337.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461864 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727228

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.068	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.081	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.76	N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.68	N
REVEL	Benign	0.17
Sift	Benign	0.11	T
Sift4G	Benign	0.14	T
Polyphen		0.0	B
Vest4		0.17
MutPred		0.56		Gain of sheet (P = 0.0827);
MVP		0.38
MPC		0.30
ClinPred		0.10	T
GERP RS		0.27
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.11
gMVP		0.42

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-44272249;