2-171793655-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_003705.5(SLC25A12):c.1418G>A(p.Arg473Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0392 in 1,613,974 control chromosomes in the GnomAD database, including 1,478 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R473W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.031 ( 104 hom., cov: 32)

Exomes 𝑓: 0.040 ( 1374 hom. )

Consequence

SLC25A12
NM_003705.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 3.30

Publications

10 publications found

Variant links:

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: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
mitochondrial disease
Inheritance: AR Classification: MODERATE Submitted by: ClinGen

SLC25A12 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.0021488369).

BP6

Variant 2-171793655-C-T is Benign according to our data. Variant chr2-171793655-C-T is described in ClinVar as Benign. ClinVar VariationId is 332339.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.031 (4723/152234) while in subpopulation NFE AF = 0.0461 (3137/68020). AF 95% confidence interval is 0.0448. There are 104 homozygotes in GnomAd4. There are 2291 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 104 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
SLC25A12	NM_003705.5 link	c.1418G>A	p.Arg473Gln	missense_variant	Exon 14 of 18	ENST00000422440.7	NP_003696.2
SLC25A12	XM_047446142.1 link	c.1145G>A	p.Arg382Gln	missense_variant	Exon 12 of 16		XP_047302098.1
SLC25A12	NR_047549.2 link	n.1332G>A		non_coding_transcript_exon_variant	Exon 13 of 17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SLC25A12	ENST00000422440.7 link	c.1418G>A	p.Arg473Gln	missense_variant	Exon 14 of 18	1	NM_003705.5	ENSP00000388658.2
SLC25A12	ENST00000263812.8 link	n.*1038G>A		non_coding_transcript_exon_variant	Exon 13 of 17	2		ENSP00000263812.4
SLC25A12	ENST00000263812.8 link	n.*1038G>A		3_prime_UTR_variant	Exon 13 of 17	2		ENSP00000263812.4

Frequencies

GnomAD3 genomes

AF:

0.0310

AC:

4723

AN:

152116

Hom.:

104

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00659

Gnomad AMI

AF:

0.0526

Gnomad AMR

AF:

0.0231

Gnomad ASJ

AF:

0.0265

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00518

Gnomad FIN

AF:

0.0690

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0461

Gnomad OTH

AF:

0.0287

GnomAD2 exomes

AF:

0.0326

AC:

8188

AN:

251348

AF XY:

0.0319

show subpopulations

Gnomad AFR exome

AF:

0.00560

Gnomad AMR exome

AF:

0.0161

Gnomad ASJ exome

AF:

0.0258

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0747

Gnomad NFE exome

AF:

0.0458

Gnomad OTH exome

AF:

0.0409

GnomAD4 exome

AF:

0.0400

AC:

58510

AN:

1461740

Hom.:

1374

Cov.:

AF XY:

0.0391

AC XY:

28467

AN XY:

727182

show subpopulations

African (AFR)

AF:

0.00511

AC:

171

AN:

33480

American (AMR)

AF:

0.0173

AC:

773

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0266

AC:

694

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00577

AC:

498

AN:

86258

European-Finnish (FIN)

AF:

0.0806

AC:

4306

AN:

53410

Middle Eastern (MID)

AF:

0.0284

AC:

164

AN:

5768

European-Non Finnish (NFE)

AF:

0.0448

AC:

49768

AN:

1111876

Other (OTH)

AF:

0.0354

AC:

2135

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

2974

5948

8922

11896

14870

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1736

3472

5208

6944

8680

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0310

AC:

4723

AN:

152234

Hom.:

104

Cov.:

AF XY:

0.0308

AC XY:

2291

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.00657

AC:

273

AN:

41546

American (AMR)

AF:

0.0231

AC:

353

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0265

AC:

AN:

3466

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.00519

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0690

AC:

731

AN:

10590

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0461

AC:

3137

AN:

68020

Other (OTH)

AF:

0.0289

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

232

464

695

927

1159

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

156

208

260

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0404

Hom.:

513

Bravo

AF:

0.0267

TwinsUK

AF:

0.0475

AC:

176

ALSPAC

AF:

0.0457

AC:

176

ESP6500AA

AF:

0.00704

AC:

ESP6500EA

AF:

0.0459

AC:

395

ExAC

AF:

0.0337

AC:

4093

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.0418

EpiControl

AF:

0.0420

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 23, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.40

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.37

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.95

MetaRNN

Benign

0.0021

MetaSVM

Benign

-0.56

MutationAssessor

Benign

1.8

PhyloP100

3.3

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-2.0

REVEL

Benign

0.27

Sift

Benign

0.053

Sift4G

Uncertain

0.025

Polyphen

0.75

Vest4

0.13

MPC

0.74

ClinPred

0.030

GERP RS

4.4

Varity_R

0.14

gMVP

0.47

Mutation Taster

=97/3

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over