NM_001191061.2:c.235G>A

Variant names:

• chr11-793587-C-T
• rs1215087087
• NM_001191061.2:c.235G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001191061.2(SLC25A22):​c.235G>A​(p.Glu79Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,459,454 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: 0.0000021 (0 hom.)
• Consequence: SLC25A22 NM_001191061.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.96
• Publications: 1 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.8

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC25A22	NM_001191061.2	c.235G>A	p.Glu79Lys	missense_variant	Exon 5 of 10	ENST00000628067.3	NP_001177990.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC25A22	ENST00000628067.3	c.235G>A	p.Glu79Lys	missense_variant	Exon 5 of 10	1	NM_001191061.2	ENSP00000486058.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249390 AF XY: 0.00000740

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1459454 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726040

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51052

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111962

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy Uncertain:1

Oct 30, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid with lysine at codon 79 of the SLC25A22 protein (p.Glu79Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual with developmental delay, seizures and hypotonia (PMID: 28255779). 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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	1.0
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	35
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.27	T;T;T;.;.;.;.;.;.;.;.;T;T;T;.;.;.
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	.;.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.80	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.0069	T
MutationAssessor	Benign	1.6	L;L;L;.;.;.;.;.;.;.;.;.;.;.;.;.;.
PhyloP100		4.0
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.9	D;.;D;D;.;D;.;D;D;D;.;D;D;.;D;D;.
REVEL	Uncertain	0.64
Sift	Uncertain	0.0010	D;.;D;D;.;D;.;D;D;D;.;D;D;.;D;D;.
Sift4G	Benign	0.14	T;T;T;D;T;.;D;D;D;.;D;.;.;.;.;.;.
Polyphen		0.99	D;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.82
MutPred		0.67		Gain of MoRF binding (P = 0.0245);Gain of MoRF binding (P = 0.0245);Gain of MoRF binding (P = 0.0245);.;Gain of MoRF binding (P = 0.0245);.;Gain of MoRF binding (P = 0.0245);Gain of MoRF binding (P = 0.0245);Gain of MoRF binding (P = 0.0245);Gain of MoRF binding (P = 0.0245);Gain of MoRF binding (P = 0.0245);Gain of MoRF binding (P = 0.0245);Gain of MoRF binding (P = 0.0245);Gain of MoRF binding (P = 0.0245);Gain of MoRF binding (P = 0.0245);Gain of MoRF binding (P = 0.0245);Gain of MoRF binding (P = 0.0245);
MVP		0.75
MPC		1.1
ClinPred		0.99	D
GERP RS		3.4
Varity_R		0.89
gMVP		0.99
Mutation Taster		=5/95	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1215087087; hg19: chr11-793587;