rs146402942

Variant names:

• chr11-794790-G-A
• rs146402942
• NM_001191061.2:c.132C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-794790-G-A
• chr11-794790-G-C

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.132C>T​(p.Arg44Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00143 in 1,598,154 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 0.00077 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (2 hom.)
• Consequence: SLC25A22 NM_001191061.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:9
• Conservation: PhyloP100: 0.758
• 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=-0.52).
• BP6: Variant 11-794790-G-A is Benign according to our data. Variant chr11-794790-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 139130.
• BP7: Synonymous conserved (PhyloP=0.758 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000775 (118/152350) while in subpopulation NFE AF = 0.00146 (99/68038). AF 95% confidence interval is 0.00122. There are 0 homozygotes in GnomAd4. There are 62 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.132C>T	p.Arg44Arg	synonymous	Exon 3 of 10	NP_001177990.1	Q9H936
	SLC25A22	NM_001425334.1		c.132C>T	p.Arg44Arg	synonymous	Exon 3 of 10	NP_001412263.1
	SLC25A22	NM_001425335.1		c.132C>T	p.Arg44Arg	synonymous	Exon 3 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.132C>T	p.Arg44Arg	synonymous	Exon 3 of 10	ENSP00000486058.1	Q9H936
	SLC25A22	ENST00000320230.9	TSL:1	c.132C>T	p.Arg44Arg	synonymous	Exon 3 of 10	ENSP00000322020.5	Q9H936
	SLC25A22	ENST00000532361.5	TSL:1	n.347C>T		non_coding_transcript_exon	Exon 3 of 4

Frequencies

GnomAD3 genomes AF: 0.000769 AC: 117 AN: 152232 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00145

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000785 AC: 175 AN: 222824 AF XY: 0.000740

Gnomad AFR exome AF: 0.0000725

Gnomad AMR exome AF: 0.000351

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000326

Gnomad NFE exome AF: 0.00135

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00150 AC: 2170 AN: 1445804 Hom.: 2 Cov.: 32 AF XY: 0.00138 AC XY: 987 AN XY: 717674

African (AFR) AF: 0.000270 AC: 9 AN: 33358

American (AMR) AF: 0.000332 AC: 14 AN: 42232

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25750

East Asian (EAS) AF: 0.00 AC: 0 AN: 39178

South Asian (SAS) AF: 0.000527 AC: 44 AN: 83540

European-Finnish (FIN) AF: 0.000508 AC: 26 AN: 51202

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4802

European-Non Finnish (NFE) AF: 0.00182 AC: 2009 AN: 1105966

Other (OTH) AF: 0.00114 AC: 68 AN: 59776

GnomAD4 genome AF: 0.000775 AC: 118 AN: 152350 Hom.: 0 Cov.: 33 AF XY: 0.000832 AC XY: 62 AN XY: 74492

African (AFR) AF: 0.000240 AC: 10 AN: 41580

American (AMR) AF: 0.00 AC: 0 AN: 15300

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4834

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00146 AC: 99 AN: 68038

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

Alfa AF: 0.000873 Hom.: 0

Bravo AF: 0.000733

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
-	1	4	not provided (5)
-	-	2	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	-0.52
CADD	Benign	16
DANN	Benign	0.91
PhyloP100		0.76
PromoterAI		0.060	Neutral
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs146402942; hg19: chr11-794790;