rs535927522

Positions:

• chr11-794798-C-A
• chr11-794798-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001425344.1(SLC25A22):​c.-200G>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.00000484 in 1,445,822 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: SLC25A22 NM_001425344.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.88

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.896

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC25A22	NM_001191061.2	c.124G>T	p.Gly42Cys	missense_variant	3/10	ENST00000628067.3	NP_001177990.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC25A22	ENST00000628067.3	c.124G>T	p.Gly42Cys	missense_variant	3/10	1	NM_001191061.2	ENSP00000486058.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000484 AC: 7 AN: 1445822 Hom.: 0 Cov.: 32 AF XY: 0.00000418 AC XY: 3 AN XY: 717638

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: 0.00000633

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000151

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

Labcorp Genetics (formerly Invitae), Labcorp

Jul 12, 2021

This sequence change replaces glycine with cysteine at codon 42 of the SLC25A22 protein (p.Gly42Cys). The glycine residue is highly conserved and there is a large physicochemical difference between glycine and cysteine. This variant is not present in population databases (ExAC no frequency). 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 disruptive. 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	Pathogenic	0.69
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T;T;T;.;.;.;.;.;.;.;.;T;T;T;.;.;.;.;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	.;.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.68	D
MutationAssessor	Pathogenic	3.1	M;M;M;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-7.5	D;.;D;D;.;D;.;D;D;D;D;D;D;.;D;D;.;D;D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D;.;D;D;.;D;.;D;D;D;D;D;D;.;D;D;.;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;.;D;D;D;.;D;.;.;.;.;.;.;.;.
Polyphen		0.95	P;P;P;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.78
MutPred		0.65		Loss of disorder (P = 0.0043);Loss of disorder (P = 0.0043);Loss of disorder (P = 0.0043);Loss of disorder (P = 0.0043);Loss of disorder (P = 0.0043);Loss of disorder (P = 0.0043);Loss of disorder (P = 0.0043);Loss of disorder (P = 0.0043);Loss of disorder (P = 0.0043);Loss of disorder (P = 0.0043);Loss of disorder (P = 0.0043);Loss of disorder (P = 0.0043);Loss of disorder (P = 0.0043);Loss of disorder (P = 0.0043);Loss of disorder (P = 0.0043);Loss of disorder (P = 0.0043);Loss of disorder (P = 0.0043);Loss of disorder (P = 0.0043);Loss of disorder (P = 0.0043);
MVP		0.76
MPC		1.2
ClinPred		1.0	D
GERP RS		3.3
Varity_R		0.98
gMVP		0.98

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: rs535927522; hg19: chr11-794798;