rs750386693

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBS1_Supporting

The NM_001191061.2(SLC25A22):c.452C>T(p.Ser151Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000219 in 1,555,648 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. S151S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

SLC25A22
NM_001191061.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 3.68

Publications

0 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.18382671).

BS1

Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.0000221 (31/1403462) while in subpopulation EAS AF = 0.000298 (11/36912). AF 95% confidence interval is 0.000167. There are 0 homozygotes in GnomAdExome4. There are 12 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC25A22	NM_001191061.2 link	c.452C>T	p.Ser151Leu	missense_variant	Exon 7 of 10	ENST00000628067.3	NP_001177990.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC25A22	ENST00000628067.3 link	c.452C>T	p.Ser151Leu	missense_variant	Exon 7 of 10	1	NM_001191061.2	ENSP00000486058.1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000500

AC:

AN:

160006

AF XY:

0.0000230

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000388

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000492

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.0000221

AC:

AN:

1403462

Hom.:

Cov.:

AF XY:

0.0000173

AC XY:

AN XY:

694418

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32310

American (AMR)

AF:

0.0000541

AC:

AN:

36974

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25332

East Asian (EAS)

AF:

0.000298

AC:

AN:

36912

South Asian (SAS)

AF:

0.00

AC:

AN:

81418

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40466

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5708

European-Non Finnish (NFE)

AF:

0.00000460

AC:

AN:

1085964

Other (OTH)

AF:

0.000223

AC:

AN:

58378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41436

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000385

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68010

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000271

Hom.:

Bravo

AF:

0.0000529

ExAC

AF:

0.00000864

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Dec 11, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.452C>T (p.S151L) alteration is located in exon 7 (coding exon 6) of the SLC25A22 gene. This alteration results from a C to T substitution at nucleotide position 452, causing the serine (S) at amino acid position 151 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Developmental and epileptic encephalopathy

Uncertain:1

Jul 11, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 151 of the SLC25A22 protein (p.Ser151Leu). This variant is present in population databases (rs750386693, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with SLC25A22-related conditions. ClinVar contains an entry for this variant (Variation ID: 461376). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Uncertain:1

May 16, 2019

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.16

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.065

T;T;T;.;.;.;.;.;.;.;.

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.31

LIST_S2

Benign

0.84

.;.;T;T;T;T;T;T;T;D;T

M_CAP

Uncertain

0.24

MetaRNN

Benign

0.18

T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.75

MutationAssessor

Benign

1.5

L;L;L;.;.;.;.;.;.;.;.

PhyloP100

3.7

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-1.9

N;.;N;N;.;N;.;.;.;.;.

REVEL

Uncertain

0.30

Sift

Benign

0.075

T;.;T;T;.;T;.;.;.;.;.

Sift4G

Benign

0.45

T;T;T;T;T;.;T;T;T;.;T

Polyphen

0.017

B;B;B;.;.;.;.;.;.;.;.

Vest4

0.51

MutPred

0.44

Loss of glycosylation at S151 (P = 0.0437);Loss of glycosylation at S151 (P = 0.0437);Loss of glycosylation at S151 (P = 0.0437);.;Loss of glycosylation at S151 (P = 0.0437);.;Loss of glycosylation at S151 (P = 0.0437);Loss of glycosylation at S151 (P = 0.0437);Loss of glycosylation at S151 (P = 0.0437);Loss of glycosylation at S151 (P = 0.0437);Loss of glycosylation at S151 (P = 0.0437);

MVP

0.65

MPC

0.45

ClinPred

0.052

GERP RS

3.4

Varity_R

0.080

gMVP

0.75

Mutation Taster

=89/11

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over