Genetic Variant SLC25A22:p.Glu60Gln (chr11-794482-C-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001191061.2(SLC25A22):c.178G>C(p.Glu60Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. E60K) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

SLC25A22
NM_001191061.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.87

Publications

1 publications found

Variant links:

Genes affected

SLC25A22 (HGNC:19954): (solute carrier family 25 member 22) This gene encodes a mitochondrial glutamate carrier. Mutations in this gene are associated with early infantile epileptic encephalopathy. Multiple alternatively spliced variants, encoding the same protein, have been identified.[provided by RefSeq, Jul 2010]

SLC25A22 Gene-Disease associations (from GenCC):

genetic developmental and epileptic encephalopathy
Inheritance: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
developmental and epileptic encephalopathy, 3
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
early myoclonic encephalopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
malignant migrating partial seizures of infancy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

SLC25A22 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.909

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001191061.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SLC25A22	NM_001191061.2	MANE Select	c.178G>C	p.Glu60Gln	missense	Exon 4 of 10	NP_001177990.1
SLC25A22	NM_001425334.1		c.253G>C	p.Glu85Gln	missense	Exon 4 of 10	NP_001412263.1
SLC25A22	NM_001425335.1		c.178G>C	p.Glu60Gln	missense	Exon 4 of 10	NP_001412264.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SLC25A22	ENST00000628067.3	TSL:1 MANE Select	c.178G>C	p.Glu60Gln	missense	Exon 4 of 10	ENSP00000486058.1
SLC25A22	ENST00000320230.9	TSL:1	c.178G>C	p.Glu60Gln	missense	Exon 4 of 10	ENSP00000322020.5
SLC25A22	ENST00000532361.5	TSL:1	n.393G>C		non_coding_transcript_exon	Exon 4 of 4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000403

AC:

AN:

248052

AF XY:

0.00000742

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000895

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000825

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.64

MetaRNN

Pathogenic

0.91

MetaSVM

Uncertain

0.64

MutationAssessor

Uncertain

2.5

PhyloP100

5.9

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-2.5

REVEL

Pathogenic

0.81

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.90

MutPred

0.79

Gain of MoRF binding (P = 0.0273)

MVP

0.77

MPC

1.1

ClinPred

0.97

GERP RS

3.3

Varity_R

0.81

gMVP

0.97

Mutation Taster

=62/38

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over