NM_003705.5:c.2009C>T

Variant names:

• chr2-171785302-G-A
• rs78523632
• NM_003705.5:c.2009C>T

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.2009C>T​(p.Pro670Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000031 in 1,613,976 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SLC25A12 NM_003705.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.59
• 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: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• 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=0.14869896).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003705.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC25A12	NM_003705.5	MANE Select	c.2009C>T	p.Pro670Leu	missense	Exon 18 of 18	NP_003696.2
	SLC25A12	NR_047549.2		n.1923C>T		non_coding_transcript_exon	Exon 17 of 17

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC25A12	ENST00000422440.7	TSL:1 MANE Select	c.2009C>T	p.Pro670Leu	missense	Exon 18 of 18	ENSP00000388658.2	O75746-1
	SLC25A12	ENST00000958780.1		c.2186C>T	p.Pro729Leu	missense	Exon 20 of 20	ENSP00000628839.1
	SLC25A12	ENST00000958781.1		c.2096C>T	p.Pro699Leu	missense	Exon 19 of 19	ENSP00000628840.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152134 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251452 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000274 AC: 4 AN: 1461842 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727226

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1112002

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152134 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74314

African (AFR) AF: 0.00 AC: 0 AN: 41434

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000530 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.045	T
BayesDel_noAF	Benign	-0.29
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Benign	0.042
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		3.6
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.33
Sift	Benign	0.048	D
Sift4G	Uncertain	0.041	D
Polyphen		0.0	B
Vest4		0.13
MVP		0.55
MPC		1.3
ClinPred		0.56	D
GERP RS		6.2
Varity_R		0.042
gMVP		0.70
Mutation Taster		=88/12	polymorphism

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: rs78523632; hg19: chr2-172641812;