rs116134953

Variant names:

• chr11-794509-C-G
• rs116134953
• NM_001191061.2:c.151G>C

Your query was ambiguous. Multiple possible variants found:

• chr11-794509-C-G
• chr11-794509-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001191061.2(SLC25A22):​c.151G>C​(p.Asp51His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,112 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. D51N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SLC25A22 NM_001191061.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.59
• Publications: 3 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC25A22	NM_001191061.2	c.151G>C	p.Asp51His	missense_variant	Exon 4 of 10	ENST00000628067.3	NP_001177990.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC25A22	ENST00000628067.3	c.151G>C	p.Asp51His	missense_variant	Exon 4 of 10	1	NM_001191061.2	ENSP00000486058.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000406 AC: 1 AN: 246498 AF XY: 0.00000746

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460112 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726328

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.00 AC: 0 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86112

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52446

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5648

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111688

Other (OTH) AF: 0.00 AC: 0 AN: 60330

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T;T;T;.;.;.;.;.;.;.;.;T;T;T;.;.;.;.;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	.;.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.37	D
MutationAssessor	Benign	1.9	L;L;L;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
PhyloP100		7.6
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-6.7	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	Benign	0.16	T;T;T;D;T;.;T;T;T;.;T;.;.;.;.;.;.;.;.
Polyphen		1.0	D;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.94
MutPred		0.79		Gain of MoRF binding (P = 0.0532);Gain of MoRF binding (P = 0.0532);Gain of MoRF binding (P = 0.0532);.;Gain of MoRF binding (P = 0.0532);Gain of MoRF binding (P = 0.0532);Gain of MoRF binding (P = 0.0532);Gain of MoRF binding (P = 0.0532);Gain of MoRF binding (P = 0.0532);Gain of MoRF binding (P = 0.0532);Gain of MoRF binding (P = 0.0532);Gain of MoRF binding (P = 0.0532);Gain of MoRF binding (P = 0.0532);Gain of MoRF binding (P = 0.0532);Gain of MoRF binding (P = 0.0532);Gain of MoRF binding (P = 0.0532);Gain of MoRF binding (P = 0.0532);Gain of MoRF binding (P = 0.0532);Gain of MoRF binding (P = 0.0532);
MVP		0.87
MPC		1.3
ClinPred		0.99	D
GERP RS		3.3
Varity_R		0.93
gMVP		0.97
Mutation Taster		=42/58	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: rs116134953; hg19: chr11-794509;