rs150242281

Positions:

• chr11-794491-C-G
• chr11-794491-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.64

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]

ACMG classification

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/exons	MANE	UniProt
SLC25A22	NM_001191061.2	c.169G>C	p.Val57Leu	missense_variant	4/10	ENST00000628067.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC25A22	ENST00000628067.3	c.169G>C	p.Val57Leu	missense_variant	4/10	1	NM_001191061.2	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152216 Hom.: 0 Cov.: 33

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: 4 AN: 1460630 Hom.: 1 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726630

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: 1 AN: 152216 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74356

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

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 15, 2022

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. 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. This variant has not been reported in the literature in individuals affected with SLC25A22-related conditions. 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.00026	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	14
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	D
M_CAP	Uncertain	0.12	D
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	T
MutationAssessor	Benign	0.97	L;L;L;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.60	T
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	T
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

Other links and lift over

dbSNP: rs150242281; hg19: chr11-794491;