Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS1

The NM_001191061.2(SLC25A22):c.414C>T(p.Ala138Ala) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000182 in 1,546,216 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

SLC25A22
NM_001191061.2 splice_region, synonymous

Scores

Splicing: ADA: 0.000009800

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: -2.91

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

genetic developmental and epileptic encephalopathy
Inheritance: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
developmental and epileptic encephalopathy, 3
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
early myoclonic encephalopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
malignant migrating partial seizures of infancy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

SLC25A22 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.63).

BP6

Variant 11-792726-G-A is Benign according to our data. Variant chr11-792726-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 207151.

BP7

Synonymous conserved (PhyloP=-2.91 with no splicing effect.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000189 (264/1394062) while in subpopulation MID AF = 0.00035 (2/5708). AF 95% confidence interval is 0.00019. There are 0 homozygotes in GnomAdExome4. There are 144 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001191061.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SLC25A22	NM_001191061.2	MANE Select	c.414C>T	p.Ala138Ala	splice_region synonymous	Exon 7 of 10	NP_001177990.1
SLC25A22	NM_001425334.1		c.489C>T	p.Ala163Ala	splice_region synonymous	Exon 7 of 10	NP_001412263.1
SLC25A22	NM_001425335.1		c.453C>T	p.Ala151Ala	synonymous	Exon 7 of 10	NP_001412264.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SLC25A22	ENST00000628067.3	TSL:1 MANE Select	c.414C>T	p.Ala138Ala	splice_region synonymous	Exon 7 of 10	ENSP00000486058.1
SLC25A22	ENST00000320230.9	TSL:1	c.414C>T	p.Ala138Ala	splice_region synonymous	Exon 7 of 10	ENSP00000322020.5
SLC25A22	ENST00000531214.5	TSL:2	c.414C>T	p.Ala138Ala	splice_region synonymous	Exon 7 of 10	ENSP00000437236.1

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000205

AC:

AN:

151098

AF XY:

0.000208

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000239

Gnomad ASJ exome

AF:

0.000117

Gnomad EAS exome

AF:

0.000257

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000326

Gnomad OTH exome

AF:

0.000228

GnomAD4 exome

AF:

0.000189

AC:

264

AN:

1394062

Hom.:

Cov.:

AF XY:

0.000209

AC XY:

144

AN XY:

689004

show subpopulations

African (AFR)

AF:

0.000125

AC:

AN:

31972

American (AMR)

AF:

0.000221

AC:

AN:

36220

Ashkenazi Jewish (ASJ)

AF:

0.0000396

AC:

AN:

25222

East Asian (EAS)

AF:

0.0000826

AC:

AN:

36302

South Asian (SAS)

AF:

0.0000248

AC:

AN:

80516

European-Finnish (FIN)

AF:

0.0000796

AC:

AN:

37706

Middle Eastern (MID)

AF:

0.000350

AC:

AN:

5708

European-Non Finnish (NFE)

AF:

0.000213

AC:

230

AN:

1082248

Other (OTH)

AF:

0.000189

AC:

AN:

58168

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000112

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41422

American (AMR)

AF:

0.0000654

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.000207

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000191

AC:

AN:

67994

Other (OTH)

AF:

0.000478

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.543

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000324

Hom.:

Bravo

AF:

0.000106

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Developmental and epileptic encephalopathy (1)

Inborn genetic diseases (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.63

CADD

Benign

0.030

(source)

DANN

Benign

0.71

PhyloP100

-2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0000098

dbscSNV1_RF

Benign

0.0060

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

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NM_001191061.2:c.414C>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over