rs776366708

Variant names:

• chr7-6023306-C-A
• rs776366708
• NM_006303.4:c.578C>A

Your query was ambiguous. Multiple possible variants found:

• chr7-6023306-C-A
• chr7-6023306-C-G
• chr7-6023306-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_006303.4(AIMP2):​c.578C>A​(p.Pro193Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000694 in 1,440,078 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P193L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: AIMP2 NM_006303.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.18
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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.578C>A	p.Pro193Gln	missense	Exon 4 of 4	NP_006294.2
	EIF2AK1	NM_014413.4	MANE Select	c.*1367G>T		3_prime_UTR	Exon 15 of 15	NP_055228.2
	AIMP2	NM_001362785.2		c.491C>A	p.Pro164Gln	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.578C>A	p.Pro193Gln	missense	Exon 4 of 4	ENSP00000223029.3	Q13155-1
	EIF2AK1	ENST00000199389.11	TSL:1 MANE Select	c.*1367G>T		3_prime_UTR	Exon 15 of 15	ENSP00000199389.6	Q9BQI3-1
	AIMP2	ENST00000395236.2	TSL:2	c.371C>A	p.Pro124Gln	missense	Exon 3 of 3	ENSP00000378658.2	Q13155-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.94e-7 AC: 1 AN: 1440078 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 715106

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32598

American (AMR) AF: 0.00 AC: 0 AN: 41882

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24868

East Asian (EAS) AF: 0.00 AC: 0 AN: 39582

South Asian (SAS) AF: 0.00 AC: 0 AN: 82980

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49802

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5616

European-Non Finnish (NFE) AF: 9.06e-7 AC: 1 AN: 1103274

Other (OTH) AF: 0.00 AC: 0 AN: 59476

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Benign	-0.26
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.039	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		6.2
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.14
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.041	D
Polyphen		0.89	P
Vest4		0.56
MutPred		0.35		Gain of catalytic residue at M197 (P = 0.0306)
MVP		0.40
MPC		0.23
ClinPred		0.93	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.53
gMVP		0.52
Mutation Taster		=60/40	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.90		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.90		Position offset: 2

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

Other links and lift over

dbSNP: rs776366708; hg19: chr7-6062937;