rs201089795

Variant names:

• chr11-792640-C-T
• rs201089795
• NM_001191061.2:c.500G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001191061.2(SLC25A22):​c.500G>A​(p.Arg167Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00112 in 1,585,920 control chromosomes in the GnomAD database, including 3 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. R167R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0023 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (3 hom.)
• Consequence: SLC25A22 NM_001191061.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 2.78
• 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), 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009172082).
• BP6: Variant 11-792640-C-T is Benign according to our data. Variant chr11-792640-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 207153.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00227 (346/152256) while in subpopulation AFR AF = 0.00578 (240/41542). AF 95% confidence interval is 0.00518. There are 0 homozygotes in GnomAd4. There are 168 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.500G>A	p.Arg167Gln	missense	Exon 7 of 10	NP_001177990.1
	SLC25A22	NM_001425334.1		c.575G>A	p.Arg192Gln	missense	Exon 7 of 10	NP_001412263.1
	SLC25A22	NM_001425335.1		c.539G>A	p.Arg180Gln	missense	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.500G>A	p.Arg167Gln	missense	Exon 7 of 10	ENSP00000486058.1
	SLC25A22	ENST00000320230.9	TSL:1	c.500G>A	p.Arg167Gln	missense	Exon 7 of 10	ENSP00000322020.5
	SLC25A22	ENST00000860087.1		c.575G>A	p.Arg192Gln	missense	Exon 7 of 10	ENSP00000530146.1

Frequencies

GnomAD3 genomes AF: 0.00226 AC: 344 AN: 152138 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00575

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00405

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000868

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.00109 AC: 214 AN: 196674 AF XY: 0.000934

Gnomad AFR exome AF: 0.00549

Gnomad AMR exome AF: 0.0000679

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000203

Gnomad FIN exome AF: 0.00333

Gnomad NFE exome AF: 0.00110

Gnomad OTH exome AF: 0.000391

GnomAD4 exome AF: 0.00100 AC: 1438 AN: 1433664 Hom.: 3 Cov.: 32 AF XY: 0.000958 AC XY: 682 AN XY: 711554

African (AFR) AF: 0.00630 AC: 208 AN: 33032

American (AMR) AF: 0.000172 AC: 7 AN: 40746

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25700

East Asian (EAS) AF: 0.000104 AC: 4 AN: 38516

South Asian (SAS) AF: 0.000143 AC: 12 AN: 83908

European-Finnish (FIN) AF: 0.00315 AC: 148 AN: 47010

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5732

European-Non Finnish (NFE) AF: 0.000907 AC: 997 AN: 1099634

Other (OTH) AF: 0.00103 AC: 61 AN: 59386

GnomAD4 genome AF: 0.00227 AC: 346 AN: 152256 Hom.: 0 Cov.: 33 AF XY: 0.00226 AC XY: 168 AN XY: 74448

African (AFR) AF: 0.00578 AC: 240 AN: 41542

American (AMR) AF: 0.000131 AC: 2 AN: 15300

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

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

European-Finnish (FIN) AF: 0.00405 AC: 43 AN: 10616

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

European-Non Finnish (NFE) AF: 0.000868 AC: 59 AN: 67996

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00120 Hom.: 0

Bravo AF: 0.00210

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00483 AC: 21

ESP6500EA AF: 0.000822 AC: 7

ExAC AF: 0.00118 AC: 140

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.078	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0092	T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	1.7	L
PhyloP100		2.8
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.29
Sift	Benign	0.033	D
Sift4G	Benign	0.077	T
Polyphen		0.24	B
Vest4		0.56
MVP		0.67
MPC		0.52
ClinPred		0.025	T
GERP RS		3.5
Varity_R		0.17
gMVP		0.83
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs201089795; hg19: chr11-792640; COSMIC: COSV107332731; COSMIC: COSV107332731;