2-171793735-T-G

Variant names:

• chr2-171793735-T-G
• rs149278617
• NM_003705.5:c.1338A>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_003705.5(SLC25A12):​c.1338A>C​(p.Pro446Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00144 in 1,614,048 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P446P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0057 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00099 (16 hom.)
• Consequence: SLC25A12 NM_003705.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.50
• Publications: 3 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 2-171793735-T-G is Benign according to our data. Variant chr2-171793735-T-G is described in ClinVar as Benign. ClinVar VariationId is 332340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.5 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0057 (868/152176) while in subpopulation AFR AF = 0.0177 (734/41512). AF 95% confidence interval is 0.0166. There are 4 homozygotes in GnomAd4. There are 429 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

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.1338A>C	p.Pro446Pro	synonymous	Exon 14 of 18	NP_003696.2
	SLC25A12	NR_047549.2		n.1252A>C		non_coding_transcript_exon	Exon 13 of 17

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC25A12	ENST00000422440.7	TSL:1 MANE Select	c.1338A>C	p.Pro446Pro	synonymous	Exon 14 of 18	ENSP00000388658.2	O75746-1
	SLC25A12	ENST00000958780.1		c.1515A>C	p.Pro505Pro	synonymous	Exon 16 of 20	ENSP00000628839.1
	SLC25A12	ENST00000958781.1		c.1338A>C	p.Pro446Pro	synonymous	Exon 14 of 19	ENSP00000628840.1

Frequencies

GnomAD3 genomes AF: 0.00571 AC: 868 AN: 152058 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0177

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00504

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000574

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00181 AC: 456 AN: 251250 AF XY: 0.00137

Gnomad AFR exome AF: 0.0161

Gnomad AMR exome AF: 0.00327

Gnomad ASJ exome AF: 0.000596

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000493

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.000993 AC: 1452 AN: 1461872 Hom.: 16 Cov.: 32 AF XY: 0.000913 AC XY: 664 AN XY: 727234

African (AFR) AF: 0.0199 AC: 665 AN: 33478

American (AMR) AF: 0.00347 AC: 155 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000727 AC: 19 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00659 AC: 38 AN: 5768

European-Non Finnish (NFE) AF: 0.000332 AC: 369 AN: 1112002

Other (OTH) AF: 0.00321 AC: 194 AN: 60394

GnomAD4 genome AF: 0.00570 AC: 868 AN: 152176 Hom.: 4 Cov.: 32 AF XY: 0.00577 AC XY: 429 AN XY: 74396

African (AFR) AF: 0.0177 AC: 734 AN: 41512

American (AMR) AF: 0.00503 AC: 77 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

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

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000574 AC: 39 AN: 67986

Other (OTH) AF: 0.00521 AC: 11 AN: 2112

Alfa AF: 0.00327 Hom.: 3

Bravo AF: 0.00660

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000818

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	SLC25A12-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.20
DANN	Benign	0.53
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs149278617; hg19: chr2-172650245;