NM_001191061.2:c.413-8G>C

Variant names:

• chr11-792735-C-G
• rs376015598
• NM_001191061.2:c.413-8G>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_001191061.2(SLC25A22):​c.413-8G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000749 in 1,545,328 control chromosomes in the GnomAD database, including 1 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 0.00065 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00076 (1 hom.)
• Consequence: SLC25A22 NM_001191061.2 splice_region, intron
• Scores: Splicing: ADA: 0.00001710
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 0.00300
• Publications: 0 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: G2P, Labcorp Genetics (formerly Invitae)
• 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 11-792735-C-G is Benign according to our data. Variant chr11-792735-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 139136.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00065 (99/152238) while in subpopulation AMR AF = 0.00176 (27/15298). AF 95% confidence interval is 0.00125. There are 0 homozygotes in GnomAd4. There are 41 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.413-8G>C		splice_region intron	N/A	NP_001177990.1	Q9H936
	SLC25A22	NM_001425335.1		c.444G>C	p.Leu148Phe	missense	Exon 7 of 10	NP_001412264.1
	SLC25A22	NM_001425336.1		c.420G>C	p.Leu140Phe	missense	Exon 7 of 10	NP_001412265.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC25A22	ENST00000628067.3	TSL:1 MANE Select	c.413-8G>C		splice_region intron	N/A	ENSP00000486058.1	Q9H936
	SLC25A22	ENST00000320230.9	TSL:1	c.413-8G>C		splice_region intron	N/A	ENSP00000322020.5	Q9H936
	SLC25A22	ENST00000860087.1		c.488-8G>C		splice_region intron	N/A	ENSP00000530146.1

Frequencies

GnomAD3 genomes AF: 0.000651 AC: 99 AN: 152120 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

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: 0.000897

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000558 AC: 84 AN: 150522 AF XY: 0.000615

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00128

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000800

Gnomad OTH exome AF: 0.000457

GnomAD4 exome AF: 0.000760 AC: 1059 AN: 1393090 Hom.: 1 Cov.: 33 AF XY: 0.000739 AC XY: 509 AN XY: 688386

African (AFR) AF: 0.000156 AC: 5 AN: 31960

American (AMR) AF: 0.00124 AC: 45 AN: 36174

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25208

East Asian (EAS) AF: 0.00 AC: 0 AN: 36240

South Asian (SAS) AF: 0.0000498 AC: 4 AN: 80288

European-Finnish (FIN) AF: 0.0000267 AC: 1 AN: 37470

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5702

European-Non Finnish (NFE) AF: 0.000879 AC: 951 AN: 1081914

Other (OTH) AF: 0.000912 AC: 53 AN: 58134

GnomAD4 genome AF: 0.000650 AC: 99 AN: 152238 Hom.: 0 Cov.: 33 AF XY: 0.000551 AC XY: 41 AN XY: 74436

African (AFR) AF: 0.000217 AC: 9 AN: 41536

American (AMR) AF: 0.00176 AC: 27 AN: 15298

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.000897 AC: 61 AN: 67980

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

Alfa AF: 0.000455 Hom.: 0

Bravo AF: 0.000812

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	Early myoclonic encephalopathy (2)
-	1	1	not provided (2)
-	-	1	Developmental and epileptic encephalopathy (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.2
DANN	Benign	0.48
PhyloP100		0.0030
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000017
dbscSNV1_RF	Benign	0.014
SpliceAI score (max)		0.020		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: rs376015598; hg19: chr11-792735;