7-6009379-G-C

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 8P and 9B. PVS1BP6BS1BS2

The NM_001326606.2(AIMP2):c.15+1G>C variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.000821 in 1,611,826 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00084 ( 3 hom. )

Consequence

AIMP2
NM_001326606.2 splice_donor, intron

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 6.14

Variant links:

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]

AIMP2 links:

PMS2 (HGNC:9122): (PMS1 homolog 2, mismatch repair system component) The protein encoded by this gene is a key component of the mismatch repair system that functions to correct DNA mismatches and small insertions and deletions that can occur during DNA replication and homologous recombination. This protein forms heterodimers with the gene product of the mutL homolog 1 (MLH1) gene to form the MutL-alpha heterodimer. The MutL-alpha heterodimer possesses an endonucleolytic activity that is activated following recognition of mismatches and insertion/deletion loops by the MutS-alpha and MutS-beta heterodimers, and is necessary for removal of the mismatched DNA. There is a DQHA(X)2E(X)4E motif found at the C-terminus of the protein encoded by this gene that forms part of the active site of the nuclease. Mutations in this gene have been associated with hereditary nonpolyposis colorectal cancer (HNPCC; also known as Lynch syndrome) and Turcot syndrome. [provided by RefSeq, Apr 2016]

PMS2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

BP6

Variant 7-6009379-G-C is Benign according to our data. Variant chr7-6009379-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 444713.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000838 (1223/1459496) while in subpopulation MID AF= 0.00603 (25/4148). AF 95% confidence interval is 0.00419. There are 3 homozygotes in gnomad4_exome. There are 636 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AIMP2	NM_006303.4 link	c.16G>C	p.Val6Leu	missense_variant	Exon 1 of 4	ENST00000223029.8	NP_006294.2	Q13155-1A0A024QZY1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AIMP2	ENST00000223029.8 link	c.16G>C	p.Val6Leu	missense_variant	Exon 1 of 4	1	NM_006303.4	ENSP00000223029.3		Q13155-1

Frequencies

GnomAD3 genomes

AF:

0.000657

AC:

100

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00634

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000882

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.00109

AC:

273

AN:

250554

Hom.:

AF XY:

0.00110

AC XY:

149

AN XY:

135682

show subpopulations

Gnomad AFR exome

AF:

0.000372

Gnomad AMR exome

AF:

0.000752

Gnomad ASJ exome

AF:

0.00786

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000948

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00108

Gnomad OTH exome

AF:

0.00180

GnomAD4 exome

AF:

0.000838

AC:

1223

AN:

1459496

Hom.:

Cov.:

AF XY:

0.000876

AC XY:

636

AN XY:

726046

show subpopulations

Gnomad4 AFR exome

AF:

0.000180

Gnomad4 AMR exome

AF:

0.000604

Gnomad4 ASJ exome

AF:

0.00681

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000986

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000715

Gnomad4 OTH exome

AF:

0.00176

GnomAD4 genome

AF:

0.000656

AC:

100

AN:

152330

Hom.:

Cov.:

AF XY:

0.000644

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00634

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000882

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.00124

Hom.:

Bravo

AF:

0.000642

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.00102

AC:

124

EpiCase

AF:

0.00185

EpiControl

AF:

0.00172

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Jan 09, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Leukodystrophy, hypomyelinating, 17

Benign:1

Feb 26, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.34

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.29

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.055

T;.

Eigen

Benign

-0.0074

Eigen_PC

Benign

0.14

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.83

T;T

M_CAP

Benign

0.014

MetaRNN

Benign

0.0086

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.1

M;M

PrimateAI

Uncertain

0.67

PROVEAN

Benign

0.44

N;N

REVEL

Benign

0.16

Sift

Benign

0.40

T;T

Sift4G

Benign

0.70

T;T

Polyphen

0.084

B;.

Vest4

0.67

MutPred

0.24

Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);

MVP

0.21

MPC

0.10

ClinPred

0.050

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.31

gMVP

0.43

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over