rs797045969

chr11-792722-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001191061.2(SLC25A22):c.418C>T(p.Gln140Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000143 in 1,394,146 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SLC25A22 NM_001191061.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.14

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-792722-G-A is Pathogenic according to our data. Variant chr11-792722-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 212198.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC25A22	NM_001191061.2	c.418C>T	p.Gln140Ter	stop_gained	7/10	ENST00000628067.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC25A22	ENST00000628067.3	c.418C>T	p.Gln140Ter	stop_gained	7/10	1	NM_001191061.2	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1394146 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 689052

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000185

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 13, 2022

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 212198). This variant has not been reported in the literature in individuals affected with SLC25A22-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln140*) in the SLC25A22 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC25A22 are known to be pathogenic (PMID: 15592994, 19780765). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 25, 2021

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge -

Early myoclonic encephalopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 02, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.60
Cadd	Pathogenic	40
Dann	Uncertain	1.0
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.93	D
MutationTaster	Benign	1.0	A;A
Vest4		0.27
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs797045969; hg19: chr11-792722;