rs1554965292

Variant names:

• chr11-792004-T-C
• rs1554965292
• NM_001191061.2:c.883A>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001191061.2(SLC25A22):​c.883A>G​(p.Ile295Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000961 in 1,456,410 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: SLC25A22 NM_001191061.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.01

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC25A22	NM_001191061.2	c.883A>G	p.Ile295Val	missense_variant	Exon 10 of 10	ENST00000628067.3	NP_001177990.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC25A22	ENST00000628067.3	c.883A>G	p.Ile295Val	missense_variant	Exon 10 of 10	1	NM_001191061.2	ENSP00000486058.1
SLC25A22	ENST00000320230.9	c.883A>G	p.Ile295Val	missense_variant	Exon 10 of 10	1		ENSP00000322020.5
SLC25A22	ENST00000531214.5	c.883A>G	p.Ile295Val	missense_variant	Exon 10 of 10	2		ENSP00000437236.1
SLC25A22	ENST00000481290.5	c.*19A>G		downstream_gene_variant		5		ENSP00000431829.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000425 AC: 1 AN: 235046 Hom.: 0 AF XY: 0.00000777 AC XY: 1 AN XY: 128768

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000962

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000961 AC: 14 AN: 1456410 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 724326

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: 0.0000126

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

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

Feb 08, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a SLC25A22-related disease. This sequence change replaces isoleucine with valine at codon 295 of the SLC25A22 protein (p.Ile295Val). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and valine. In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.014	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.041	T;T;T
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	.;.;D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.44	T;T;T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	0.47	N;N;N
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.85	N;.;N
REVEL	Uncertain	0.54
Sift	Benign	0.16	T;.;T
Sift4G	Benign	0.17	T;T;T
Polyphen		1.0	D;D;D
Vest4		0.50
MutPred		0.55		Gain of methylation at R291 (P = 0.1117);Gain of methylation at R291 (P = 0.1117);Gain of methylation at R291 (P = 0.1117);
MVP		0.37
MPC		1.1
ClinPred		0.59	D
GERP RS		3.9
Varity_R		0.19
gMVP		0.37

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: rs1554965292; hg19: chr11-792004;