chr2-171834750-C-G

Variant names:

• chr2-171834750-C-G
• rs35881803
• NM_003705.5:c.728G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003705.5(SLC25A12):​c.728G>C​(p.Arg243Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R243K) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC25A12 NM_003705.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.88
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2596504).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC25A12	NM_003705.5	c.728G>C	p.Arg243Thr	missense_variant	Exon 7 of 18	ENST00000422440.7	NP_003696.2
SLC25A12	XM_047446142.1	c.455G>C	p.Arg152Thr	missense_variant	Exon 5 of 16		XP_047302098.1
SLC25A12	NR_047549.2	n.642G>C		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	c.728G>C	p.Arg243Thr	missense_variant	Exon 7 of 18	1	NM_003705.5	ENSP00000388658.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.17	T
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.46	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		4.9
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.36
Sift	Benign	0.18	T
Sift4G	Benign	0.41	T
Polyphen		0.21	B
Vest4		0.35
MutPred		0.38		Loss of MoRF binding (P = 0.0668);
MVP		0.74
MPC		1.1
ClinPred		0.74	D
GERP RS		5.5
Varity_R		0.32
gMVP		0.78
Mutation Taster		=42/58	disease causing

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

Other links and lift over

dbSNP: rs35881803; hg19: chr2-172691260;