rs111277421

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001191061.2(SLC25A22):c.448C>G(p.Leu150Val) variant causes a missense change. The variant allele was found at a frequency of 0.0744 in 1,553,550 control chromosomes in the GnomAD database, including 4,773 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.060 ( 322 hom., cov: 33)

Exomes 𝑓: 0.076 ( 4451 hom. )

Consequence

SLC25A22
NM_001191061.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 3.86

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0020220578).

BP6

Variant 11-792692-G-C is Benign according to our data. Variant chr11-792692-G-C is described in ClinVar as [Benign]. Clinvar id is 139137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-792692-G-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0827 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC25A22	NM_001191061.2 linkuse as main transcript	c.448C>G	p.Leu150Val	missense_variant	7/10	ENST00000628067.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC25A22	ENST00000628067.3 linkuse as main transcript	c.448C>G	p.Leu150Val	missense_variant	7/10	1	NM_001191061.2	P1

Frequencies

GnomAD3 genomes

AF:

0.0601

AC:

9153

AN:

152174

Hom.:

322

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0408

Gnomad AMI

AF:

0.0822

Gnomad AMR

AF:

0.0398

Gnomad ASJ

AF:

0.0634

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0167

Gnomad FIN

AF:

0.0540

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0846

Gnomad OTH

AF:

0.0680

GnomAD3 exomes

AF:

0.0526

AC:

8328

AN:

158250

Hom.:

245

AF XY:

0.0520

AC XY:

4479

AN XY:

86114

show subpopulations

Gnomad AFR exome

AF:

0.0428

Gnomad AMR exome

AF:

0.0290

Gnomad ASJ exome

AF:

0.0606

Gnomad EAS exome

AF:

0.000248

Gnomad SAS exome

AF:

0.0196

Gnomad FIN exome

AF:

0.0572

Gnomad NFE exome

AF:

0.0831

Gnomad OTH exome

AF:

0.0638

GnomAD4 exome

AF:

0.0759

AC:

106389

AN:

1401258

Hom.:

4451

Cov.:

AF XY:

0.0748

AC XY:

51858

AN XY:

693128

show subpopulations

Gnomad4 AFR exome

AF:

0.0401

Gnomad4 AMR exome

AF:

0.0315

Gnomad4 ASJ exome

AF:

0.0627

Gnomad4 EAS exome

AF:

0.000109

Gnomad4 SAS exome

AF:

0.0212

Gnomad4 FIN exome

AF:

0.0581

Gnomad4 NFE exome

AF:

0.0867

Gnomad4 OTH exome

AF:

0.0687

GnomAD4 genome

AF:

0.0601

AC:

9148

AN:

152292

Hom.:

322

Cov.:

AF XY:

0.0572

AC XY:

4260

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.0406

Gnomad4 AMR

AF:

0.0397

Gnomad4 ASJ

AF:

0.0634

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.0168

Gnomad4 FIN

AF:

0.0540

Gnomad4 NFE

AF:

0.0845

Gnomad4 OTH

AF:

0.0668

Alfa

AF:

0.0730

Hom.:

102

Bravo

AF:

0.0586

TwinsUK

AF:

0.0866

AC:

321

ALSPAC

AF:

0.0872

AC:

336

ESP6500AA

AF:

0.0345

AC:

147

ESP6500EA

AF:

0.0726

AC:

607

ExAC

AF:

0.0372

AC:

4254

Asia WGS

AF:

0.00953

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 12, 2012	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 27, 2014	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 08, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Early infantile epileptic encephalopathy with suppression bursts

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

May 04, 2018

- -

Early myoclonic encephalopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.21

Cadd

Benign

Dann

Benign

0.62

DEOGEN2

Benign

0.038

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

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.40

FATHMM_MKL

Uncertain

0.96

MetaRNN

Benign

0.0020

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

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.4

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

MutationTaster

Benign

0.63

N;N

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.49

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

REVEL

Benign

0.22

Sift

Benign

0.51

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

Sift4G

Benign

0.36

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

Polyphen

0.0020

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

Vest4

0.17

MPC

0.45

ClinPred

0.0043

GERP RS

3.4

Varity_R

0.077

gMVP

0.70

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