rs535927522

Variant names:

• chr11-794798-C-A
• rs535927522
• NM_001191061.2:c.124G>T

Your query was ambiguous. Multiple possible variants found:

• chr11-794798-C-A
• chr11-794798-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_001191061.2(SLC25A22):​c.124G>T​(p.Gly42Cys) variant causes a missense 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G42S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: SLC25A22 NM_001191061.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.88
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• genetic developmental and epileptic encephalopathy

  Inheritance: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• developmental and epileptic encephalopathy, 3

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• early myoclonic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• malignant migrating partial seizures of infancy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.896

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC25A22	NM_001191061.2	c.124G>T	p.Gly42Cys	missense_variant	Exon 3 of 10	ENST00000628067.3	NP_001177990.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC25A22	ENST00000628067.3	c.124G>T	p.Gly42Cys	missense_variant	Exon 3 of 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

African (AFR) AF: 0.00 AC: 0 AN: 33358

American (AMR) AF: 0.00 AC: 0 AN: 42108

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25752

East Asian (EAS) AF: 0.00 AC: 0 AN: 39180

South Asian (SAS) AF: 0.00 AC: 0 AN: 83532

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4944

European-Non Finnish (NFE) AF: 0.00000633 AC: 7 AN: 1105788

Other (OTH) AF: 0.00 AC: 0 AN: 59792

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy Uncertain:1

Jul 12, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 disruptive. This variant has not been reported in the literature in individuals affected with SLC25A22-related conditions. This variant is not present in population databases (ExAC no frequency). 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. -

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;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
PhyloP100		5.9
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
PromoterAI		0.0066	Neutral
Varity_R		0.98
gMVP		0.98
Mutation Taster		=32/68	disease causing

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

Other links and lift over

dbSNP: rs535927522; hg19: chr11-794798;