2-171791578-C-T

Position:

• chr2-171791578-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_003705.5(SLC25A12):​c.1458G>A​(p.Ala486=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00466 in 1,613,902 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0047 (25 hom.)
• Consequence: SLC25A12 NM_003705.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0250

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.26).
• BP6: Variant 2-171791578-C-T is Benign according to our data. Variant chr2-171791578-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 332338.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.025 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00391 (595/152204) while in subpopulation NFE AF= 0.00576 (392/68010). AF 95% confidence interval is 0.00529. There are 2 homozygotes in gnomad4. There are 304 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC25A12	NM_003705.5	c.1458G>A	p.Ala486=	synonymous_variant	15/18	ENST00000422440.7	NP_003696.2
SLC25A12	XM_047446142.1	c.1185G>A	p.Ala395=	synonymous_variant	13/16		XP_047302098.1
SLC25A12	NR_047549.2	n.1372G>A		non_coding_transcript_exon_variant	14/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC25A12	ENST00000422440.7	c.1458G>A	p.Ala486=	synonymous_variant	15/18	1	NM_003705.5	ENSP00000388658	P1
SLC25A12	ENST00000263812.8	c.*1078G>A		3_prime_UTR_variant, NMD_transcript_variant	14/17	2		ENSP00000263812

Frequencies

GnomAD3 genomes AF: 0.00391 AC: 595 AN: 152086 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000942

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00576

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00357 AC: 898 AN: 251458 Hom.: 3 AF XY: 0.00368 AC XY: 500 AN XY: 135902

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.00150

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00245

Gnomad FIN exome AF: 0.00993

Gnomad NFE exome AF: 0.00448

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.00473 AC: 6921 AN: 1461698 Hom.: 25 Cov.: 31 AF XY: 0.00464 AC XY: 3375 AN XY: 727166

Gnomad4 AFR exome AF: 0.000896

Gnomad4 AMR exome AF: 0.00143

Gnomad4 ASJ exome AF: 0.00115

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00265

Gnomad4 FIN exome AF: 0.00945

Gnomad4 NFE exome AF: 0.00520

Gnomad4 OTH exome AF: 0.00450

GnomAD4 genome AF: 0.00391 AC: 595 AN: 152204 Hom.: 2 Cov.: 32 AF XY: 0.00409 AC XY: 304 AN XY: 74410

Gnomad4 AFR AF: 0.000939

Gnomad4 AMR AF: 0.00288

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00208

Gnomad4 FIN AF: 0.00943

Gnomad4 NFE AF: 0.00576

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00472 Hom.: 2

Bravo AF: 0.00280

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00551

EpiControl AF: 0.00314

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	SLC25A12: BP4, BP7 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

SLC25A12-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 01, 2024

This variant is classified as 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
BayesDel_noAF	Benign	-0.26
CADD	Benign	10
DANN	Benign	0.58

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

LitVar

Other links and lift over

dbSNP: rs142179562; hg19: chr2-172648088; COSMIC: COSV99785628; COSMIC: COSV99785628;