rs147840220

chr11-792555-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS1

The NM_001191061.2(SLC25A22):c.585C>T(p.Leu195=) 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:4 B:6
• Conservation: PhyloP100: 0.995

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 -8 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=4, Benign=2, Uncertain_significance=4}.
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC25A22	NM_001191061.2	c.585C>T	p.Leu195=	splice_region_variant, synonymous_variant	7/10	ENST00000628067.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC25A22	ENST00000628067.3	c.585C>T	p.Leu195=	splice_region_variant, synonymous_variant	7/10	1	NM_001191061.2	P1

Frequencies

GnomAD3 genomes AF: 0.000947 AC: 144 AN: 152068 Hom.: 0 Cov.: 33

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.: 1 AF XY: 0.000615 AC XY: 82 AN XY: 133274

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.: 3 Cov.: 32 AF XY: 0.00197 AC XY: 1430 AN XY: 726364

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.: 0 Cov.: 33 AF XY: 0.000714 AC XY: 53 AN XY: 74272

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.: 0

Bravo AF: 0.000975

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:2

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	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2021	- -

not specified Uncertain:1 Benign: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

Invitae

Jan 24, 2024

- -

SLC25A22-related disorder Benign:1

Likely benign, criteria provided, single submitter

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	15
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

Other links and lift over

dbSNP: rs147840220; hg19: chr11-792555;