11-792692-G-A

Variant names:

• chr11-792692-G-A
• rs111277421
• NM_001191061.2:c.448C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001191061.2(SLC25A22):​c.448C>T​(p.Leu150Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000000714 in 1,401,284 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L150V) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: SLC25A22 NM_001191061.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.86
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33274198).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC25A22	NM_001191061.2	c.448C>T	p.Leu150Phe	missense_variant	Exon 7 of 10	ENST00000628067.3	NP_001177990.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC25A22	ENST00000628067.3	c.448C>T	p.Leu150Phe	missense_variant	Exon 7 of 10	1	NM_001191061.2	ENSP00000486058.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.14e-7 AC: 1 AN: 1401284 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 693142

African (AFR) AF: 0.00 AC: 0 AN: 32242

American (AMR) AF: 0.00 AC: 0 AN: 36808

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25298

East Asian (EAS) AF: 0.00 AC: 0 AN: 36768

South Asian (SAS) AF: 0.00 AC: 0 AN: 81278

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39938

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5706

European-Non Finnish (NFE) AF: 9.22e-7 AC: 1 AN: 1084894

Other (OTH) AF: 0.00 AC: 0 AN: 58352

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.057	T;T;T;.;.;.;.;.;.;.;.
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.59	.;.;T;T;T;T;T;T;T;T;T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.33	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	1.5	L;L;L;.;.;.;.;.;.;.;.
PhyloP100		3.9
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.4	N;.;N;N;.;N;.;.;.;.;.
REVEL	Benign	0.28
Sift	Benign	0.080	T;.;T;T;.;T;.;.;.;.;.
Sift4G	Benign	0.28	T;T;T;T;T;.;T;T;D;.;D
Polyphen		0.81	P;P;P;.;.;.;.;.;.;.;.
Vest4		0.34
MutPred		0.31		Gain of catalytic residue at L150 (P = 0.0087);Gain of catalytic residue at L150 (P = 0.0087);Gain of catalytic residue at L150 (P = 0.0087);.;Gain of catalytic residue at L150 (P = 0.0087);.;Gain of catalytic residue at L150 (P = 0.0087);Gain of catalytic residue at L150 (P = 0.0087);Gain of catalytic residue at L150 (P = 0.0087);Gain of catalytic residue at L150 (P = 0.0087);Gain of catalytic residue at L150 (P = 0.0087);
MVP		0.54
MPC		0.44
ClinPred		0.66	D
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.70
Mutation Taster		=76/24	polymorphism

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: rs111277421; hg19: chr11-792692;