rs121918334

Positions:

chr11-792429-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_001191061.2(SLC25A22):c.617C>T(p.Pro206Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,338 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

SLC25A22
NM_001191061.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 7.76

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.92

PP5

Variant 11-792429-G-A is Pathogenic according to our data. Variant chr11-792429-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1775.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC25A22	NM_001191061.2 linkuse as main transcript	c.617C>T	p.Pro206Leu	missense_variant	8/10	ENST00000628067.3	NP_001177990.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC25A22	ENST00000628067.3 linkuse as main transcript	c.617C>T	p.Pro206Leu	missense_variant	8/10	1	NM_001191061.2	ENSP00000486058	P1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

249926

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135422

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461148

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726876

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000648

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 31, 2022

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SLC25A22 function (PMID: 25033742). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SLC25A22 protein function. ClinVar contains an entry for this variant (Variation ID: 1775). This missense change has been observed in individuals with SLC25A22-related conditions (PMID: 15592994, 25033742). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs121918334, gnomAD 0.01%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 206 of the SLC25A22 protein (p.Pro206Leu). -

Early myoclonic encephalopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Dec 03, 2018

The homozygous p.Pro206Leu variant in SLC25A22 was identified by our study in one individual with Epileptic Encephalopathy. This variant has been identified in the literature in four affected siblings. Functional assays showed mutant functionality to be 20% of wild-type. (Molinari et al. 2005, PMID: 15592994). This variant has been identified in <0.01% (2/15258) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121918334). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. -

Developmental and epileptic encephalopathy, 3

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2005

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

T;T;T;.;.

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

1.0

.;.;D;D;D

M_CAP

Pathogenic

0.80

MetaRNN

Pathogenic

0.92

D;D;D;D;D

MetaSVM

Uncertain

0.13

MutationAssessor

Benign

1.9

L;L;L;.;.

MutationTaster

Benign

1.0

A;A

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-9.3

D;.;D;D;.

REVEL

Pathogenic

0.69

Sift

Pathogenic

0.0

D;.;D;D;.

Sift4G

Benign

0.091

T;T;T;T;T

Polyphen

1.0

D;D;D;.;.

Vest4

0.94

MVP

0.85

MPC

1.2

ClinPred

0.99

GERP RS

2.9

Varity_R

0.97

gMVP

0.88

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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