chr11-792570-G-A

Variant names:

• chr11-792570-G-A
• rs145322467
• NM_001191061.2:c.570C>T

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.570C>T​(p.Leu190Leu) 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
• Publications: 3 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=-0.54).
• 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 VariationId is 139139.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 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.570C>T	p.Leu190Leu	synonymous	Exon 7 of 10	NP_001177990.1	Q9H936
	SLC25A22	NM_001425334.1		c.645C>T	p.Leu215Leu	synonymous	Exon 7 of 10	NP_001412263.1
	SLC25A22	NM_001425335.1		c.609C>T	p.Leu203Leu	synonymous	Exon 7 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.570C>T	p.Leu190Leu	synonymous	Exon 7 of 10	ENSP00000486058.1	Q9H936
	SLC25A22	ENST00000320230.9	TSL:1	c.570C>T	p.Leu190Leu	synonymous	Exon 7 of 10	ENSP00000322020.5	Q9H936
	SLC25A22	ENST00000937625.1		c.562C>T	p.Arg188Trp	missense	Exon 7 of 10	ENSP00000607684.1

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

GnomAD2 exomes AF: 0.00189 AC: 460 AN: 243588 AF XY: 0.00200

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 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

African (AFR) AF: 0.000658 AC: 22 AN: 33444

American (AMR) AF: 0.00406 AC: 181 AN: 44636

Ashkenazi Jewish (ASJ) AF: 0.0000766 AC: 2 AN: 26100

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39674

South Asian (SAS) AF: 0.000162 AC: 14 AN: 86222

European-Finnish (FIN) AF: 0.000500 AC: 26 AN: 51976

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5768

European-Non Finnish (NFE) AF: 0.00322 AC: 3585 AN: 1111760

Other (OTH) AF: 0.00239 AC: 144 AN: 60338

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

African (AFR) AF: 0.000651 AC: 27 AN: 41470

American (AMR) AF: 0.00615 AC: 94 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.000472 AC: 5 AN: 10604

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.00288 AC: 196 AN: 67948

Other (OTH) AF: 0.00332 AC: 7 AN: 2110

Alfa AF: 0.000683 Hom.: 0

Bravo AF: 0.00235

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	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	-0.54
CADD	Benign	3.4
DANN	Benign	0.81
PhyloP100		-0.38
Mutation Taster		=100/0	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: rs145322467; hg19: chr11-792570; COSMIC: COSV100204142; COSMIC: COSV100204142;