chr2-171837270-G-A

Variant names:

• chr2-171837270-G-A
• rs3765166
• NM_003705.5:c.466-3C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003705.5(SLC25A12):​c.466-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.252 in 1,613,082 control chromosomes in the GnomAD database, including 55,169 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (4195 hom., cov: 32)
  • Exomes 𝑓: 0.26 (50974 hom.)
• Consequence: SLC25A12 NM_003705.5 splice_region, intron
• Scores: Splicing: ADA: 0.001212
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.360
• Publications: 14 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 2-171837270-G-A is Benign according to our data. Variant chr2-171837270-G-A is described in ClinVar as Benign. ClinVar VariationId is 332344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.555 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC25A12	NM_003705.5	c.466-3C>T		splice_region_variant, intron_variant	Intron 5 of 17	ENST00000422440.7	NP_003696.2
SLC25A12	NR_047549.2	n.380-3C>T		splice_region_variant, intron_variant	Intron 4 of 16
SLC25A12	XM_047446142.1	c.193-3C>T		splice_region_variant, intron_variant	Intron 3 of 15		XP_047302098.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC25A12	ENST00000422440.7	c.466-3C>T		splice_region_variant, intron_variant	Intron 5 of 17	1	NM_003705.5	ENSP00000388658.2
SLC25A12	ENST00000263812.8	n.*86-3C>T		splice_region_variant, intron_variant	Intron 4 of 16	2		ENSP00000263812.4
SLC25A12	ENST00000426896.5	n.570-3C>T		splice_region_variant, intron_variant	Intron 6 of 8	2		ENSP00000413968.1
SLC25A12	ENST00000475360.6	n.*183-3C>T		splice_region_variant, intron_variant	Intron 7 of 7	5		ENSP00000437845.1

Frequencies

GnomAD3 genomes AF: 0.214 AC: 32573 AN: 151976 Hom.: 4198 Cov.: 32

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.145

Gnomad AMR AF: 0.172

Gnomad ASJ AF: 0.278

Gnomad EAS AF: 0.573

Gnomad SAS AF: 0.305

Gnomad FIN AF: 0.268

Gnomad MID AF: 0.229

Gnomad NFE AF: 0.248

Gnomad OTH AF: 0.222

GnomAD2 exomes AF: 0.264 AC: 66341 AN: 251024 AF XY: 0.270

Gnomad AFR exome AF: 0.0981

Gnomad AMR exome AF: 0.166

Gnomad ASJ exome AF: 0.283

Gnomad EAS exome AF: 0.575

Gnomad FIN exome AF: 0.269

Gnomad NFE exome AF: 0.254

Gnomad OTH exome AF: 0.262

GnomAD4 exome AF: 0.256 AC: 374156 AN: 1460988 Hom.: 50974 Cov.: 34 AF XY: 0.258 AC XY: 187549 AN XY: 726846

African (AFR) AF: 0.0916 AC: 3066 AN: 33462

American (AMR) AF: 0.168 AC: 7503 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.285 AC: 7442 AN: 26130

East Asian (EAS) AF: 0.562 AC: 22298 AN: 39684

South Asian (SAS) AF: 0.306 AC: 26375 AN: 86240

European-Finnish (FIN) AF: 0.273 AC: 14585 AN: 53378

Middle Eastern (MID) AF: 0.250 AC: 1442 AN: 5760

European-Non Finnish (NFE) AF: 0.248 AC: 275945 AN: 1111256

Other (OTH) AF: 0.257 AC: 15500 AN: 60370

GnomAD4 genome AF: 0.214 AC: 32554 AN: 152094 Hom.: 4195 Cov.: 32 AF XY: 0.218 AC XY: 16196 AN XY: 74346

African (AFR) AF: 0.101 AC: 4174 AN: 41514

American (AMR) AF: 0.172 AC: 2629 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.278 AC: 965 AN: 3470

East Asian (EAS) AF: 0.572 AC: 2956 AN: 5164

South Asian (SAS) AF: 0.305 AC: 1468 AN: 4820

European-Finnish (FIN) AF: 0.268 AC: 2829 AN: 10568

Middle Eastern (MID) AF: 0.226 AC: 66 AN: 292

European-Non Finnish (NFE) AF: 0.248 AC: 16873 AN: 67956

Other (OTH) AF: 0.219 AC: 462 AN: 2112

Alfa AF: 0.241 Hom.: 21598

Bravo AF: 0.204

Asia WGS AF: 0.356 AC: 1241 AN: 3476

EpiCase AF: 0.248

EpiControl AF: 0.251

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 23, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	6.3
DANN	Benign	0.37
PhyloP100		0.36
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0012
dbscSNV1_RF	Benign	0.016
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: rs3765166; hg19: chr2-172693780; COSMIC: COSV55536150; COSMIC: COSV55536150;