chr11-792925-G-C

Variant names:

• chr11-792925-G-C
• rs748285057
• NM_001191061.2:c.357C>G

Variant summary

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

The ENST00000628067.3(SLC25A22):​c.357C>G​(p.Ile119Met) 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 1,461,138 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. I119I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SLC25A22 ENST00000628067.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.18
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41873908).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000628067.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC25A22	NM_001191061.2	MANE Select	c.357C>G	p.Ile119Met	missense	Exon 6 of 10	NP_001177990.1
	SLC25A22	NM_001425334.1		c.432C>G	p.Ile144Met	missense	Exon 6 of 10	NP_001412263.1
	SLC25A22	NM_001425335.1		c.357C>G	p.Ile119Met	missense	Exon 6 of 10	NP_001412264.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC25A22	ENST00000628067.3	TSL:1 MANE Select	c.357C>G	p.Ile119Met	missense	Exon 6 of 10	ENSP00000486058.1
	SLC25A22	ENST00000320230.9	TSL:1	c.357C>G	p.Ile119Met	missense	Exon 6 of 10	ENSP00000322020.5
	SLC25A22	ENST00000531214.5	TSL:2	c.357C>G	p.Ile119Met	missense	Exon 6 of 10	ENSP00000437236.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 250060 AF XY: 0.00000737

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: 0.00000887

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461138 Hom.: 0 Cov.: 38 AF XY: 0.00000138 AC XY: 1 AN XY: 726888

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

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52782

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111942

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	5.6
DANN	Benign	0.97
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.75
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.27	N
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Benign	0.42	T
MetaSVM	Uncertain	0.11	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		-1.2
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.50
Sift	Benign	0.051	T
Sift4G	Uncertain	0.0080	D
Polyphen		0.99	D
Vest4		0.78
MutPred		0.48		Gain of catalytic residue at I119 (P = 0.0216)
MVP		0.52
MPC		1.2
ClinPred		0.55	D
GERP RS		-6.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.42
gMVP		0.93
Mutation Taster		=54/46	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: rs748285057; hg19: chr11-792925;