rs147840220

Positions:

chr11-792555-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_ModerateBP6BP7BS1BS2

The NM_001191061.2(SLC25A22):c.585C>T(p.Leu195Leu) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00197 in 1,612,180 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00095 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0021 ( 3 hom. )

Consequence

SLC25A22
NM_001191061.2 splice_region, synonymous

Scores

Splicing: ADA: 0.1325

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:6

Conservation

PhyloP100: 0.995

Variant links:

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 links:

SLC25A22 (HGNC:):

SLC25A22 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.45).

BP6

Variant 11-792555-G-A is Benign according to our data. Variant chr11-792555-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 139140.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=4, Benign=2}.

BP7

Synonymous conserved (PhyloP=0.995 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000947 (144/152068) while in subpopulation NFE AF= 0.0019 (129/67980). AF 95% confidence interval is 0.00163. There are 0 homozygotes in gnomad4. There are 53 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC25A22	NM_001191061.2 linkuse as main transcript	c.585C>T	p.Leu195Leu	splice_region_variant, synonymous_variant	7/10	ENST00000628067.3	NP_001177990.1	Q9H936

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC25A22	ENST00000628067.3 linkuse as main transcript	c.585C>T	p.Leu195Leu	splice_region_variant, synonymous_variant	7/10	1	NM_001191061.2	ENSP00000486058.1		Q9H936

Frequencies

GnomAD3 genomes

AF:

0.000947

AC:

144

AN:

152068

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00190

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000692

AC:

169

AN:

244260

Hom.:

AF XY:

0.000615

AC XY:

AN XY:

133274

show subpopulations

Gnomad AFR exome

AF:

0.000709

Gnomad AMR exome

AF:

0.000378

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00128

Gnomad OTH exome

AF:

0.00100

GnomAD4 exome

AF:

0.00207

AC:

3028

AN:

1460112

Hom.:

Cov.:

AF XY:

0.00197

AC XY:

1430

AN XY:

726364

show subpopulations

Gnomad4 AFR exome

AF:

0.000329

Gnomad4 AMR exome

AF:

0.000246

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000192

Gnomad4 NFE exome

AF:

0.00260

Gnomad4 OTH exome

AF:

0.00191

GnomAD4 genome

AF:

0.000947

AC:

144

AN:

152068

Hom.:

Cov.:

AF XY:

0.000714

AC XY:

AN XY:

74272

show subpopulations

Gnomad4 AFR

AF:

0.000290

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00190

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00150

Hom.:

Bravo

AF:

0.000975

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	SLC25A22: BP4, BP7 -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 06, 2018	The c.585C>T; p.Leu195Leu variant (rs147840220, ClinVar variant ID 139140) does not alter the amino acid sequence of the SLC25A22 protein and computational splice site prediction algorithms do not predict a change in the nearest splice site or creation of a cryptic splice site. This variant has not been reported in association with mitochondrial disease in medical literature or in gene specific variation databases. This variant is listed in the genome Aggregation Database (gnomAD) with a non-Finnish European population frequency of 0.1% (identified on 172 out of 122,410 chromosomes). Based on the available information, the c.585C>T variant is likely to be benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 01, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 20, 2015	- -

not specified

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 06, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 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. -

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

May 15, 2018

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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

- -

SLC25A22-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 20, 2021

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

-0.45

CADD

Benign

DANN

Benign

0.73

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.13

dbscSNV1_RF

Benign

0.50

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over