rs147840220

Variant names:

• chr11-792555-G-A
• rs147840220
• NM_001191061.2:c.585C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

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:4 B:6
• Conservation: PhyloP100: 0.995
• 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 -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 VariationId is 139140.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 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.585C>T	p.Leu195Leu	splice_region synonymous	Exon 7 of 10	NP_001177990.1	Q9H936
	SLC25A22	NM_001425334.1		c.660C>T	p.Leu220Leu	splice_region synonymous	Exon 7 of 10	NP_001412263.1
	SLC25A22	NM_001425335.1		c.624C>T	p.Leu208Leu	splice_region 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.585C>T	p.Leu195Leu	splice_region synonymous	Exon 7 of 10	ENSP00000486058.1	Q9H936
	SLC25A22	ENST00000320230.9	TSL:1	c.585C>T	p.Leu195Leu	splice_region synonymous	Exon 7 of 10	ENSP00000322020.5	Q9H936
	SLC25A22	ENST00000937625.1		c.577C>T	p.Gln193*	stop_gained splice_region	Exon 7 of 10	ENSP00000607684.1

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

GnomAD2 exomes AF: 0.000692 AC: 169 AN: 244260 AF XY: 0.000615

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 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

African (AFR) AF: 0.000329 AC: 11 AN: 33442

American (AMR) AF: 0.000246 AC: 11 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86230

European-Finnish (FIN) AF: 0.0000192 AC: 1 AN: 52038

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00260 AC: 2888 AN: 1111828

Other (OTH) AF: 0.00191 AC: 115 AN: 60348

GnomAD4 genome AF: 0.000947 AC: 144 AN: 152068 Hom.: 0 Cov.: 33 AF XY: 0.000714 AC XY: 53 AN XY: 74272

African (AFR) AF: 0.000290 AC: 12 AN: 41406

American (AMR) AF: 0.000196 AC: 3 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00190 AC: 129 AN: 67980

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00150 Hom.: 0

Bravo AF: 0.000975

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	2	not provided (4)
-	1	1	not specified (2)
-	-	1	Developmental and epileptic encephalopathy (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	-0.45
CADD	Benign	15
DANN	Benign	0.73
PhyloP100		0.99
Mutation Taster		=63/37	polymorphism

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

Other links and lift over

dbSNP: rs147840220; hg19: chr11-792555;