2-171785338-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_003705.5(SLC25A12):c.1973C>T(p.Pro658Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P658P) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

SLC25A12
NM_003705.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.97

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.884

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SLC25A12	NM_003705.5 linkuse as main transcript	c.1973C>T	p.Pro658Leu	missense_variant	18/18	ENST00000422440.7
SLC25A12	XM_047446142.1 linkuse as main transcript	c.1700C>T	p.Pro567Leu	missense_variant	16/16
SLC25A12	NR_047549.2 linkuse as main transcript	n.1887C>T		non_coding_transcript_exon_variant	17/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC25A12	ENST00000422440.7 linkuse as main transcript	c.1973C>T	p.Pro658Leu	missense_variant	18/18	1	NM_003705.5	P1	O75746-1
SLC25A12	ENST00000472070.1 linkuse as main transcript	n.1383C>T		non_coding_transcript_exon_variant	3/3	2
SLC25A12	ENST00000263812.8 linkuse as main transcript	c.*1593C>T		3_prime_UTR_variant, NMD_transcript_variant	17/17	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251484

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1461854

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000899

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000370

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 04, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 658 of the SLC25A12 protein (p.Pro658Leu). This variant is present in population databases (rs754742634, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with SLC25A12-related conditions. ClinVar contains an entry for this variant (Variation ID: 1051699). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Pathogenic

0.16

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Uncertain

0.63

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.88

MetaSVM

Uncertain

0.68

MutationAssessor

Pathogenic

3.0

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-9.0

REVEL

Uncertain

0.59

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0050

Polyphen

1.0

Vest4

0.73

MutPred

0.60

Loss of glycosylation at P658 (P = 0.0459);

MVP

0.89

MPC

1.6

ClinPred

1.0

GERP RS

6.2

Varity_R

0.87

gMVP

0.92

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over