dbSNP rs150242281: SLC25A22:p.Val57Leu (chr11-794491-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001191061.2(SLC25A22):c.169G>C(p.Val57Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,612,846 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V57I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000027 ( 1 hom. )

Consequence

SLC25A22
NM_001191061.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.64

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.118290514).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC25A22	NM_001191061.2 link	c.169G>C	p.Val57Leu	missense_variant	Exon 4 of 10	ENST00000628067.3	NP_001177990.1	Q9H936

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC25A22	ENST00000628067.3 link	c.169G>C	p.Val57Leu	missense_variant	Exon 4 of 10	1	NM_001191061.2	ENSP00000486058.1		Q9H936

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152216

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:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1460630

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726630

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:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts

Uncertain:1

Aug 15, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 57 of the SLC25A22 protein (p.Val57Leu). This variant has not been reported in the literature in individuals affected with SLC25A22-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.00026

BayesDel_noAF

Benign

-0.24

CADD

Benign

DANN

Benign

0.83

DEOGEN2

Benign

0.040

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

Eigen

Benign

-0.93

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.85

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

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.12

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

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.97

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

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-0.60

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

REVEL

Uncertain

0.29

Sift

Benign

0.47

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

Sift4G

Benign

0.68

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

Polyphen

0.0020

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

Vest4

0.37

MutPred

0.50

Loss of methylation at R58 (P = 0.1246);Loss of methylation at R58 (P = 0.1246);Loss of methylation at R58 (P = 0.1246);.;Loss of methylation at R58 (P = 0.1246);Loss of methylation at R58 (P = 0.1246);Loss of methylation at R58 (P = 0.1246);Loss of methylation at R58 (P = 0.1246);Loss of methylation at R58 (P = 0.1246);Loss of methylation at R58 (P = 0.1246);Loss of methylation at R58 (P = 0.1246);Loss of methylation at R58 (P = 0.1246);Loss of methylation at R58 (P = 0.1246);Loss of methylation at R58 (P = 0.1246);Loss of methylation at R58 (P = 0.1246);Loss of methylation at R58 (P = 0.1246);Loss of methylation at R58 (P = 0.1246);Loss of methylation at R58 (P = 0.1246);Loss of methylation at R58 (P = 0.1246);

MVP

0.49

MPC

0.38

ClinPred

0.16

GERP RS

0.83

Varity_R

0.048

gMVP

0.92

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