rs35881803

Positions:

• chr2-171834750-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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. 12/20 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.88

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC25A12	NM_003705.5	c.728G>A	p.Arg243Lys	missense_variant	7/18	ENST00000422440.7	NP_003696.2
SLC25A12	XM_047446142.1	c.455G>A	p.Arg152Lys	missense_variant	5/16		XP_047302098.1
SLC25A12	NR_047549.2	n.642G>A		non_coding_transcript_exon_variant	6/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC25A12	ENST00000422440.7	c.728G>A	p.Arg243Lys	missense_variant	7/18	1	NM_003705.5	ENSP00000388658.2

Frequencies

GnomAD3 genomes AF: 0.0111 AC: 1683 AN: 152156 Hom.: 18 Cov.: 32

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

GnomAD3 exomes AF: 0.0111 AC: 2776 AN: 251038 Hom.: 26 AF XY: 0.0119 AC XY: 1611 AN XY: 135684

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 SAS exome AF: 0.0141

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.: 32 AF XY: 0.0165 AC XY: 12010 AN XY: 726930

Gnomad4 AFR exome AF: 0.00281

Gnomad4 AMR exome AF: 0.00483

Gnomad4 ASJ exome AF: 0.00291

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0146

Gnomad4 FIN exome AF: 0.00462

Gnomad4 NFE exome AF: 0.0193

Gnomad4 OTH exome AF: 0.0133

GnomAD4 genome AF: 0.0110 AC: 1681 AN: 152274 Hom.: 18 Cov.: 32 AF XY: 0.0107 AC XY: 793 AN XY: 74452

Gnomad4 AFR AF: 0.00387

Gnomad4 AMR AF: 0.00870

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.0131

Gnomad4 FIN AF: 0.00340

Gnomad4 NFE AF: 0.0185

Gnomad4 OTH AF: 0.00900

Alfa AF: 0.0148 Hom.: 37

Bravo AF: 0.0105

TwinsUK AF: 0.0194 AC: 72

ALSPAC AF: 0.0252 AC: 97

ESP6500AA AF: 0.00363 AC: 16

ESP6500EA AF: 0.0166 AC: 143

ExAC AF: 0.0112 AC: 1363

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.0157

EpiControl AF: 0.0165

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 23, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.10	T
Eigen	Benign	0.066
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0065	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Uncertain	2.4	M
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.71	N
REVEL	Benign	0.27
Sift	Benign	0.28	T
Sift4G	Benign	0.67	T
Polyphen		0.0040	B
Vest4		0.072
MPC		0.60
ClinPred		0.023	T
GERP RS		5.5
Varity_R		0.30
gMVP		0.67

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: rs35881803; hg19: chr2-172691260;