rs80335370

chr11-793588-G-Achr11-793588-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001191061.2(SLC25A22):c.234C>T(p.Pro78=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.12 in 1,611,342 control chromosomes in the GnomAD database, including 12,370 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P78P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.094 (762 hom., cov: 32)
  • Exomes 𝑓: 0.12 (11608 hom.)
• Consequence: SLC25A22 NM_001191061.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.35

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 Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 11-793588-G-A is Benign according to our data. Variant chr11-793588-G-A is described in ClinVar as [Benign]. Clinvar id is 159913.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.36 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.129 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC25A22	NM_001191061.2	c.234C>T	p.Pro78=	synonymous_variant	5/10	ENST00000628067.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC25A22	ENST00000628067.3	c.234C>T	p.Pro78=	synonymous_variant	5/10	1	NM_001191061.2	P1

Frequencies

GnomAD3 genomes AF: 0.0941 AC: 14308 AN: 152044 Hom.: 763 Cov.: 32

Gnomad AFR AF: 0.0444

Gnomad AMI AF: 0.0857

Gnomad AMR AF: 0.0915

Gnomad ASJ AF: 0.0568

Gnomad EAS AF: 0.0624

Gnomad SAS AF: 0.0825

Gnomad FIN AF: 0.0925

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.131

Gnomad OTH AF: 0.0784

GnomAD3 exomes AF: 0.0965 AC: 24059 AN: 249224 Hom.: 1350 AF XY: 0.0984 AC XY: 13286 AN XY: 134954

Gnomad AFR exome AF: 0.0420

Gnomad AMR exome AF: 0.0675

Gnomad ASJ exome AF: 0.0626

Gnomad EAS exome AF: 0.0641

Gnomad SAS exome AF: 0.0751

Gnomad FIN exome AF: 0.0992

Gnomad NFE exome AF: 0.127

Gnomad OTH exome AF: 0.0988

GnomAD4 exome AF: 0.122 AC: 178487 AN: 1459180 Hom.: 11608 Cov.: 32 AF XY: 0.121 AC XY: 87839 AN XY: 725874

Gnomad4 AFR exome AF: 0.0394

Gnomad4 AMR exome AF: 0.0693

Gnomad4 ASJ exome AF: 0.0642

Gnomad4 EAS exome AF: 0.0675

Gnomad4 SAS exome AF: 0.0789

Gnomad4 FIN exome AF: 0.0996

Gnomad4 NFE exome AF: 0.136

Gnomad4 OTH exome AF: 0.107

GnomAD4 genome AF: 0.0940 AC: 14310 AN: 152162 Hom.: 762 Cov.: 32 AF XY: 0.0915 AC XY: 6809 AN XY: 74386

Gnomad4 AFR AF: 0.0444

Gnomad4 AMR AF: 0.0911

Gnomad4 ASJ AF: 0.0568

Gnomad4 EAS AF: 0.0624

Gnomad4 SAS AF: 0.0817

Gnomad4 FIN AF: 0.0925

Gnomad4 NFE AF: 0.131

Gnomad4 OTH AF: 0.0823

Alfa AF: 0.0944 Hom.: 385

Bravo AF: 0.0898

Asia WGS AF: 0.0940 AC: 324 AN: 3478

EpiCase AF: 0.121

EpiControl AF: 0.123

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 07, 2018	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 18, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Early infantile epileptic encephalopathy with suppression bursts Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Early myoclonic encephalopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
Cadd	Benign	0.44
Dann	Benign	0.89

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

Publications

LitVar

Other links and lift over

dbSNP: rs80335370; hg19: chr11-793588; COSMIC: COSV57192934; COSMIC: COSV57192934;