rs145322467

Positions:

• chr11-792570-G-A
• chr11-792570-G-C
• chr11-792570-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001191061.2(SLC25A22):​c.570C>T​(p.Leu190=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00268 in 1,611,990 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L190L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0022 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0027 (8 hom.)
• Consequence: SLC25A22 NM_001191061.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: -0.382

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 11-792570-G-A is Benign according to our data. Variant chr11-792570-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 139139.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=1, Benign=3}. Variant chr11-792570-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.382 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00219 (333/152072) while in subpopulation AMR AF= 0.00615 (94/15286). AF 95% confidence interval is 0.00514. There are 2 homozygotes in gnomad4. There are 154 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC25A22	NM_001191061.2	c.570C>T	p.Leu190=	synonymous_variant	7/10	ENST00000628067.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC25A22	ENST00000628067.3	c.570C>T	p.Leu190=	synonymous_variant	7/10	1	NM_001191061.2	P1

Frequencies

GnomAD3 genomes AF: 0.00220 AC: 334 AN: 151956 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000653

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00616

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00290

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00189 AC: 460 AN: 243588 Hom.: 1 AF XY: 0.00200 AC XY: 266 AN XY: 133078

Gnomad AFR exome AF: 0.000653

Gnomad AMR exome AF: 0.00379

Gnomad ASJ exome AF: 0.000102

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.000142

Gnomad NFE exome AF: 0.00271

Gnomad OTH exome AF: 0.00268

GnomAD4 exome AF: 0.00273 AC: 3987 AN: 1459918 Hom.: 8 Cov.: 32 AF XY: 0.00259 AC XY: 1879 AN XY: 726280

Gnomad4 AFR exome AF: 0.000658

Gnomad4 AMR exome AF: 0.00406

Gnomad4 ASJ exome AF: 0.0000766

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.000500

Gnomad4 NFE exome AF: 0.00322

Gnomad4 OTH exome AF: 0.00239

GnomAD4 genome AF: 0.00219 AC: 333 AN: 152072 Hom.: 2 Cov.: 33 AF XY: 0.00207 AC XY: 154 AN XY: 74334

Gnomad4 AFR AF: 0.000651

Gnomad4 AMR AF: 0.00615

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.000472

Gnomad4 NFE AF: 0.00288

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.000683 Hom.: 0

Bravo AF: 0.00235

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 14, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	SLC25A22: BP4, BP7, BS2 -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 30, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 24, 2015	- -

Early myoclonic encephalopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 07, 2016

This alteration is classified as likely 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

- -

Developmental and epileptic encephalopathy, 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Sep 15, 2023

- -

SLC25A22-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 21, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	3.4
DANN	Benign	0.81

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: rs145322467; hg19: chr11-792570; COSMIC: COSV100204142; COSMIC: COSV100204142;