chr2-171855970-T-C

Variant names:

• chr2-171855970-T-C
• rs2056202
• NM_003705.5:c.210-21A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003705.5(SLC25A12):​c.210-21A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.838 in 1,321,958 control chromosomes in the GnomAD database, including 469,296 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.77 (46204 hom., cov: 32)
  • Exomes 𝑓: 0.85 (423092 hom.)
• Consequence: SLC25A12 NM_003705.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.65
• Publications: 37 publications found

Genes affected

SLC25A12 (HGNC:10982): (solute carrier family 25 member 12) This gene encodes a calcium-binding mitochondrial carrier protein. The encoded protein localizes to the mitochondria and is involved in the exchange of aspartate for glutamate across the inner mitochondrial membrane. Polymorphisms in this gene may be associated with autism, and mutations in this gene may also be a cause of global cerebral hypomyelination. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, Apr 2012]

SLC25A12 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 39

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• mitochondrial disease

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but rather VUS (scored 4 / 10). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 2-171855970-T-C is Benign according to our data. Variant chr2-171855970-T-C is described in ClinVar as Benign. ClinVar VariationId is 1332979.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.873 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003705.5. 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
	SLC25A12	NM_003705.5	MANE Select	c.210-21A>G		intron	N/A	NP_003696.2
	SLC25A12	NR_047549.2		n.240-11462A>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC25A12	ENST00000422440.7	TSL:1 MANE Select	c.210-21A>G		intron	N/A	ENSP00000388658.2	O75746-1
	SLC25A12	ENST00000958780.1		c.210-21A>G		intron	N/A	ENSP00000628839.1
	SLC25A12	ENST00000958781.1		c.210-21A>G		intron	N/A	ENSP00000628840.1

Frequencies

GnomAD3 genomes AF: 0.771 AC: 117165 AN: 152040 Hom.: 46203 Cov.: 32

Gnomad AFR AF: 0.609

Gnomad AMI AF: 0.759

Gnomad AMR AF: 0.676

Gnomad ASJ AF: 0.868

Gnomad EAS AF: 0.894

Gnomad SAS AF: 0.830

Gnomad FIN AF: 0.824

Gnomad MID AF: 0.861

Gnomad NFE AF: 0.862

Gnomad OTH AF: 0.793

GnomAD2 exomes AF: 0.805 AC: 202129 AN: 250994 AF XY: 0.818

Gnomad AFR exome AF: 0.597

Gnomad AMR exome AF: 0.612

Gnomad ASJ exome AF: 0.872

Gnomad EAS exome AF: 0.892

Gnomad FIN exome AF: 0.819

Gnomad NFE exome AF: 0.863

Gnomad OTH exome AF: 0.820

GnomAD4 exome AF: 0.847 AC: 991242 AN: 1169800 Hom.: 423092 Cov.: 16 AF XY: 0.849 AC XY: 506422 AN XY: 596750

African (AFR) AF: 0.601 AC: 16614 AN: 27626

American (AMR) AF: 0.618 AC: 27399 AN: 44348

Ashkenazi Jewish (ASJ) AF: 0.872 AC: 21187 AN: 24288

East Asian (EAS) AF: 0.897 AC: 34350 AN: 38308

South Asian (SAS) AF: 0.835 AC: 67118 AN: 80390

European-Finnish (FIN) AF: 0.824 AC: 43866 AN: 53224

Middle Eastern (MID) AF: 0.853 AC: 4447 AN: 5216

European-Non Finnish (NFE) AF: 0.868 AC: 733894 AN: 845806

Other (OTH) AF: 0.837 AC: 42367 AN: 50594

GnomAD4 genome AF: 0.770 AC: 117199 AN: 152158 Hom.: 46204 Cov.: 32 AF XY: 0.770 AC XY: 57279 AN XY: 74374

African (AFR) AF: 0.609 AC: 25245 AN: 41472

American (AMR) AF: 0.676 AC: 10325 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.868 AC: 3012 AN: 3472

East Asian (EAS) AF: 0.894 AC: 4632 AN: 5180

South Asian (SAS) AF: 0.829 AC: 4000 AN: 4824

European-Finnish (FIN) AF: 0.824 AC: 8729 AN: 10596

Middle Eastern (MID) AF: 0.864 AC: 254 AN: 294

European-Non Finnish (NFE) AF: 0.862 AC: 58646 AN: 68018

Other (OTH) AF: 0.787 AC: 1664 AN: 2114

Alfa AF: 0.839 Hom.: 30801

Bravo AF: 0.753

Asia WGS AF: 0.825 AC: 2871 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Developmental and epileptic encephalopathy, 39 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	18
DANN	Benign	0.84
PhyloP100		2.6
BranchPoint Hunter		4.0
Mutation Taster		=34/66	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs2056202; hg19: chr2-172712480;