rs142912356

chr2-171787879-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_003705.5(SLC25A12):c.1654G>A(p.Ala552Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000619 in 1,614,216 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00056 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00062 (9 hom.)
• Consequence: SLC25A12 NM_003705.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 4.92

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011983365).
• BP6: Variant 2-171787879-C-T is Benign according to our data. Variant chr2-171787879-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 546880.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=3}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000564 (86/152354) while in subpopulation SAS AF= 0.0029 (14/4828). AF 95% confidence interval is 0.00175. There are 0 homozygotes in gnomad4. There are 38 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC25A12	NM_003705.5	c.1654G>A	p.Ala552Thr	missense_variant	16/18	ENST00000422440.7
SLC25A12	XM_047446142.1	c.1381G>A	p.Ala461Thr	missense_variant	14/16
SLC25A12	NR_047549.2	n.1568G>A		non_coding_transcript_exon_variant	15/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC25A12	ENST00000422440.7	c.1654G>A	p.Ala552Thr	missense_variant	16/18	1	NM_003705.5	P1
SLC25A12	ENST00000472070.1	n.1064G>A		non_coding_transcript_exon_variant	1/3	2
SLC25A12	ENST00000263812.8	c.*1274G>A		3_prime_UTR_variant, NMD_transcript_variant	15/17	2

Frequencies

GnomAD3 genomes AF: 0.000565 AC: 86 AN: 152236 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000676

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000696 AC: 175 AN: 251444 Hom.: 2 AF XY: 0.000876 AC XY: 119 AN XY: 135896

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00238

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00307

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000457

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000625 AC: 913 AN: 1461862 Hom.: 9 Cov.: 32 AF XY: 0.000722 AC XY: 525 AN XY: 727236

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00233

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00388

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000429

Gnomad4 OTH exome AF: 0.000480

GnomAD4 genome AF: 0.000564 AC: 86 AN: 152354 Hom.: 0 Cov.: 32 AF XY: 0.000510 AC XY: 38 AN XY: 74508

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00374

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000676

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000599 Hom.: 0

Bravo AF: 0.000416

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000708 AC: 86

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2022	SLC25A12: BS1:Supporting -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 30, 2022	BS2 -

Developmental and epileptic encephalopathy, 39 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 11, 2021	- -

SLC25A12-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 10, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.20
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.011
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	0.41	N
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.90	N
REVEL	Uncertain	0.33
Sift	Benign	0.33	T
Sift4G	Benign	0.39	T
Polyphen		0.33	B
Vest4		0.28
MVP		0.63
MPC		0.88
ClinPred		0.037	T
GERP RS		5.5
Varity_R		0.13
gMVP		0.71

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

Other links and lift over

dbSNP: rs142912356; hg19: chr2-172644389; COSMIC: COSV55533462;