2-171834750-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.728G>A(p.Arg243Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0161 in 1,613,566 control chromosomes in the GnomAD database, including 269 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 18 hom., cov: 32)

Exomes 𝑓: 0.017 ( 251 hom. )

Consequence

SLC25A12
NM_003705.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 4.88

Publications

9 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=0.0064843595).

BP6

Variant 2-171834750-C-T is Benign according to our data. Variant chr2-171834750-C-T is described in ClinVar as Benign. ClinVar VariationId is 239551.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 = 0.011 (1681/152274) while in subpopulation NFE AF = 0.0185 (1260/68022). AF 95% confidence interval is 0.0177. There are 18 homozygotes in GnomAd4. There are 793 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC25A12	NM_003705.5 link	c.728G>A	p.Arg243Lys	missense_variant	Exon 7 of 18	ENST00000422440.7	NP_003696.2	O75746-1
SLC25A12	XM_047446142.1 link	c.455G>A	p.Arg152Lys	missense_variant	Exon 5 of 16		XP_047302098.1
SLC25A12	NR_047549.2 link	n.642G>A		non_coding_transcript_exon_variant	Exon 6 of 17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC25A12	ENST00000422440.7 link	c.728G>A	p.Arg243Lys	missense_variant	Exon 7 of 18	1	NM_003705.5	ENSP00000388658.2		O75746-1

Frequencies

GnomAD3 genomes

AF:

0.0111

AC:

1683

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00389

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00871

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.0135

Gnomad FIN

AF:

0.00340

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0185

Gnomad OTH

AF:

0.00910

GnomAD2 exomes

AF:

0.0111

AC:

2776

AN:

251038

AF XY:

0.0119

show subpopulations

Gnomad AFR exome

AF:

0.00338

Gnomad AMR exome

AF:

0.00451

Gnomad ASJ exome

AF:

0.00298

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00397

Gnomad NFE exome

AF:

0.0172

Gnomad OTH exome

AF:

0.00931

GnomAD4 exome

AF:

0.0166

AC:

24221

AN:

1461292

Hom.:

251

Cov.:

AF XY:

0.0165

AC XY:

12010

AN XY:

726930

show subpopulations

African (AFR)

AF:

0.00281

AC:

AN:

33470

American (AMR)

AF:

0.00483

AC:

216

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00291

AC:

AN:

26124

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39678

South Asian (SAS)

AF:

0.0146

AC:

1259

AN:

86252

European-Finnish (FIN)

AF:

0.00462

AC:

245

AN:

53084

Middle Eastern (MID)

AF:

0.00988

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0193

AC:

21469

AN:

1111826

Other (OTH)

AF:

0.0133

AC:

804

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

1209

2418

3627

4836

6045

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

804

1608

2412

3216

4020

<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:

0.0110

AC:

1681

AN:

152274

Hom.:

Cov.:

AF XY:

0.0107

AC XY:

793

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.00387

AC:

161

AN:

41560

American (AMR)

AF:

0.00870

AC:

133

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3466

East Asian (EAS)

AF:

0.000578

AC:

AN:

5190

South Asian (SAS)

AF:

0.0131

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00340

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0185

AC:

1260

AN:

68022

Other (OTH)

AF:

0.00900

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

162

244

325

406

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0148

Hom.:

Bravo

AF:

0.0105

TwinsUK

AF:

0.0194

AC:

ALSPAC

AF:

0.0252

AC:

ESP6500AA

AF:

0.00363

AC:

ESP6500EA

AF:

0.0166

AC:

143

ExAC

AF:

0.0112

AC:

1363

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.0157

EpiControl

AF:

0.0165

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 23, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.10

Eigen

Benign

0.066

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.86

MetaRNN

Benign

0.0065

MetaSVM

Benign

-0.61

MutationAssessor

Uncertain

2.4

PhyloP100

4.9

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.71

REVEL

Benign

0.27

Sift

Benign

0.28

Sift4G

Benign

0.67

Polyphen

0.0040

Vest4

0.072

MPC

0.60

ClinPred

0.023

GERP RS

5.5

Varity_R

0.30

gMVP

0.67

Mutation Taster

=81/19

polymorphism

(source)

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

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