NM_006303.4:c.654C>G

Variant names:

• chr7-6023382-C-G
• NM_006303.4:c.654C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_006303.4(AIMP2):​c.654C>G​(p.Phe218Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: AIMP2 NM_006303.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.33
• Publications: 0 publications found

Genes affected

AIMP2 (HGNC:20609): (aminoacyl tRNA synthetase complex interacting multifunctional protein 2) The protein encoded by this gene is part of the aminoacyl-tRNA synthetase complex, which contains nine different aminoacyl-tRNA synthetases and three non-enzymatic factors. The encoded protein is one of the non-enzymatic factors and is required for assembly and stability of the complex. [provided by RefSeq, May 2016]

EIF2AK1 (HGNC:24921): (eukaryotic translation initiation factor 2 alpha kinase 1) The protein encoded by this gene acts at the level of translation initiation to downregulate protein synthesis in response to stress. The encoded protein is a kinase that can be inactivated by hemin. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2008]

EIF2AK1 Gene-Disease associations (from GenCC):

• leukoencephalopathy, motor delay, spasticity, and dysarthria syndrome

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006303.4. 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
	AIMP2	NM_006303.4	MANE Select	c.654C>G	p.Phe218Leu	missense	Exon 4 of 4	NP_006294.2
	EIF2AK1	NM_014413.4	MANE Select	c.*1291G>C		3_prime_UTR	Exon 15 of 15	NP_055228.2
	AIMP2	NM_001362785.2		c.567C>G	p.Phe189Leu	missense	Exon 5 of 5	NP_001349714.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AIMP2	ENST00000223029.8	TSL:1 MANE Select	c.654C>G	p.Phe218Leu	missense	Exon 4 of 4	ENSP00000223029.3	Q13155-1
	EIF2AK1	ENST00000199389.11	TSL:1 MANE Select	c.*1291G>C		3_prime_UTR	Exon 15 of 15	ENSP00000199389.6	Q9BQI3-1
	AIMP2	ENST00000395236.2	TSL:2	c.447C>G	p.Phe149Leu	missense	Exon 3 of 3	ENSP00000378658.2	Q13155-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Benign	-0.039	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.088	T
Eigen	Benign	0.18
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.47	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		1.3
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.16
Sift	Benign	0.29	T
Sift4G	Benign	0.17	T
Polyphen		0.98	D
Vest4		0.65
MutPred		0.34		Gain of loop (P = 0.3485)
MVP		0.30
MPC		0.14
ClinPred		0.79	D
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.30
gMVP		0.72
Mutation Taster		=38/62	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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

hg19: chr7-6063013;