11-792954-C-G

Variant names:

• chr11-792954-C-G
• rs587777243
• NM_001191061.2:c.328G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001191061.2(SLC25A22):​c.328G>C​(p.Gly110Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,180 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 Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SLC25A22 NM_001191061.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.62
• Publications: 2 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 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 11-792954-C-G is Pathogenic according to our data. Variant chr11-792954-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 120308.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC25A22	NM_001191061.2	c.328G>C	p.Gly110Arg	missense_variant	Exon 6 of 10	ENST00000628067.3	NP_001177990.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC25A22	ENST00000628067.3	c.328G>C	p.Gly110Arg	missense_variant	Exon 6 of 10	1	NM_001191061.2	ENSP00000486058.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461180 Hom.: 0 Cov.: 38 AF XY: 0.00000138 AC XY: 1 AN XY: 726924

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52778

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111974

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Developmental and epileptic encephalopathy, 3 Pathogenic:1

Dec 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D;D;D;.;.;.;.;.;.;.;.;D;T;T;.
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.060
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.95	.;.;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	3.3	M;M;M;.;.;.;.;.;.;.;.;.;.;.;.
PhyloP100		2.6
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-7.9	D;.;D;D;.;D;.;.;D;D;.;D;D;.;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;.;D;D;.;D;.;.;D;D;.;D;D;.;D
Sift4G	Uncertain	0.059	T;T;T;T;D;.;D;D;D;.;D;.;.;.;.
Polyphen		0.99	D;D;D;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.97
MutPred		0.93		Gain of methylation at G110 (P = 0.0295);Gain of methylation at G110 (P = 0.0295);Gain of methylation at G110 (P = 0.0295);.;Gain of methylation at G110 (P = 0.0295);.;Gain of methylation at G110 (P = 0.0295);Gain of methylation at G110 (P = 0.0295);Gain of methylation at G110 (P = 0.0295);Gain of methylation at G110 (P = 0.0295);Gain of methylation at G110 (P = 0.0295);Gain of methylation at G110 (P = 0.0295);Gain of methylation at G110 (P = 0.0295);Gain of methylation at G110 (P = 0.0295);Gain of methylation at G110 (P = 0.0295);
MVP		0.91
MPC		1.3
ClinPred		1.0	D
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.92
gMVP		1.0
Mutation Taster		=4/96	disease causing (ClinVar)

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: rs587777243; hg19: chr11-792954;