chr12-39864817-T-C

Variant names:

• chr12-39864817-T-C
• rs778090097
• NM_052885.4:c.1264A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_052885.4(SLC2A13):​c.1264A>G​(p.Ile422Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,900 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SLC2A13 NM_052885.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.153
• Publications: 1 publications found

Genes affected

SLC2A13 (HGNC:15956): (solute carrier family 2 member 13) Enables ATPase binding activity; myo-inositol:proton symporter activity; and protease binding activity. Involved in myo-inositol transport and positive regulation of amyloid-beta formation. Is integral component of plasma membrane. Part of cell body; cell periphery; and cell projection. [provided by Alliance of Genome Resources, Apr 2022]

REDIC1 (HGNC:26846): (regulator of DNA class I crossover intermediates 1)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.045212418).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC2A13	NM_052885.4	c.1264A>G	p.Ile422Val	missense_variant	Exon 6 of 10	ENST00000280871.9	NP_443117.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC2A13	ENST00000280871.9	c.1264A>G	p.Ile422Val	missense_variant	Exon 6 of 10	1	NM_052885.4	ENSP00000280871.4
REDIC1	ENST00000468200.2	n.*999-42817T>C		intron_variant	Intron 18 of 18	1		ENSP00000473371.1
SLC2A13	ENST00000465517.1	n.150A>G		non_coding_transcript_exon_variant	Exon 2 of 3	2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152096 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

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: 0.0000199 AC: 5 AN: 251486 AF XY: 0.0000147

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

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: 1461804 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727212

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111948

Other (OTH) AF: 0.00 AC: 0 AN: 60392

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152096 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74294

African (AFR) AF: 0.0000483 AC: 2 AN: 41412

American (AMR) AF: 0.00 AC: 0 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1264A>G (p.I422V) alteration is located in exon 6 (coding exon 6) of the SLC2A13 gene. This alteration results from a A to G substitution at nucleotide position 1264, causing the isoleucine (I) at amino acid position 422 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	3.3
DANN	Benign	0.68
DEOGEN2	Benign	0.057	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.045	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.14	N
PhyloP100		0.15
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.16	N
REVEL	Benign	0.22
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.20
MutPred		0.46		Gain of ubiquitination at K425 (P = 0.0872);
MVP		0.14
MPC		0.19
ClinPred		0.0062	T
GERP RS		-0.66
Varity_R		0.042
gMVP		0.58
Mutation Taster		=97/3	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: rs778090097; hg19: chr12-40258619;