11-792011-C-T

Variant names:

• chr11-792011-C-T
• rs146300431
• NM_001191061.2:c.876G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001191061.2(SLC25A22):​c.876G>A​(p.Ala292Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00106 in 1,607,226 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00062 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (2 hom.)
• Consequence: SLC25A22 NM_001191061.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:9
• Conservation: PhyloP100: -0.615
• Publications: 1 publications found

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), PanelApp Australia, G2P
• early myoclonic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• malignant migrating partial seizures of infancy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 11-792011-C-T is Benign according to our data. Variant chr11-792011-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 139145.
• BP7: Synonymous conserved (PhyloP=-0.615 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000623 (95/152366) while in subpopulation SAS AF = 0.00165 (8/4834). AF 95% confidence interval is 0.000848. There are 0 homozygotes in GnomAd4. There are 51 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR,AD gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC25A22	NM_001191061.2	MANE Select	c.876G>A	p.Ala292Ala	synonymous	Exon 10 of 10	NP_001177990.1	Q9H936
	SLC25A22	NM_001425334.1		c.951G>A	p.Ala317Ala	synonymous	Exon 10 of 10	NP_001412263.1
	SLC25A22	NM_001425335.1		c.915G>A	p.Ala305Ala	synonymous	Exon 10 of 10	NP_001412264.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC25A22	ENST00000628067.3	TSL:1 MANE Select	c.876G>A	p.Ala292Ala	synonymous	Exon 10 of 10	ENSP00000486058.1	Q9H936
	SLC25A22	ENST00000320230.9	TSL:1	c.876G>A	p.Ala292Ala	synonymous	Exon 10 of 10	ENSP00000322020.5	Q9H936
	SLC25A22	ENST00000860087.1		c.951G>A	p.Ala317Ala	synonymous	Exon 10 of 10	ENSP00000530146.1

Frequencies

GnomAD3 genomes AF: 0.000624 AC: 95 AN: 152248 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00104

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000735 AC: 170 AN: 231152 AF XY: 0.000830

Gnomad AFR exome AF: 0.000425

Gnomad AMR exome AF: 0.000270

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000580

Gnomad FIN exome AF: 0.0000509

Gnomad NFE exome AF: 0.00107

Gnomad OTH exome AF: 0.00105

GnomAD4 exome AF: 0.00110 AC: 1605 AN: 1454860 Hom.: 2 Cov.: 31 AF XY: 0.00110 AC XY: 793 AN XY: 723386

African (AFR) AF: 0.0000901 AC: 3 AN: 33292

American (AMR) AF: 0.000341 AC: 15 AN: 44042

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25994

East Asian (EAS) AF: 0.00 AC: 0 AN: 39332

South Asian (SAS) AF: 0.00129 AC: 110 AN: 85478

European-Finnish (FIN) AF: 0.000155 AC: 8 AN: 51626

Middle Eastern (MID) AF: 0.00184 AC: 10 AN: 5426

European-Non Finnish (NFE) AF: 0.00127 AC: 1409 AN: 1109590

Other (OTH) AF: 0.000832 AC: 50 AN: 60080

GnomAD4 genome AF: 0.000623 AC: 95 AN: 152366 Hom.: 0 Cov.: 33 AF XY: 0.000685 AC XY: 51 AN XY: 74506

African (AFR) AF: 0.000216 AC: 9 AN: 41584

American (AMR) AF: 0.000326 AC: 5 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00165 AC: 8 AN: 4834

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00104 AC: 71 AN: 68026

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00116 Hom.: 0

Bravo AF: 0.000688

Asia WGS AF: 0.000577 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	3	not specified (3)
-	-	1	Developmental and epileptic encephalopathy (1)
-	-	1	Developmental and epileptic encephalopathy, 3 (1)
-	1	-	Early myoclonic encephalopathy (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	SLC25A22-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	6.7
DANN	Benign	0.93
PhyloP100		-0.61
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs146300431; hg19: chr11-792011;