rs759515813

Variant names:

• chr3-11029242-A-C
• rs759515813
• NM_003042.4:c.1213A>C

Your query was ambiguous. Multiple possible variants found:

• chr3-11029242-A-C
• chr3-11029242-A-G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PM2 BP6_Moderate

The NM_003042.4(SLC6A1):​c.1213A>C​(p.Ile405Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I405V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC6A1 NM_003042.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 6.17
• Publications: 0 publications found

Genes affected

SLC6A1 (HGNC:11042): (solute carrier family 6 member 1) The protein encoded by this gene is a gamma-aminobutyric acid (GABA) transporter that localizes to the plasma membrane. The encoded protein removes GABA from the synaptic cleft, restoring it to presynaptic terminals. [provided by RefSeq, Jan 2017]

SLC6A1 Gene-Disease associations (from GenCC):

• epilepsy with myoclonic atonic seizures

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Illumina, G2P, Labcorp Genetics (formerly Invitae)
• myoclonic-astatic epilepsy

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_003042.4
• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 3-11029242-A-C is Benign according to our data. Variant chr3-11029242-A-C is described in ClinVar as Benign. ClinVar VariationId is 1167091.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A1	NM_003042.4	c.1213A>C	p.Ile405Leu	missense_variant	Exon 12 of 16	ENST00000287766.10	NP_003033.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A1	ENST00000287766.10	c.1213A>C	p.Ile405Leu	missense_variant	Exon 12 of 16	1	NM_003042.4	ENSP00000287766.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Epilepsy with myoclonic atonic seizures Benign:1

Oct 05, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T;T;T;T;T;.;T;.;T;T;T;T;.;T;T;T;.;T;T;T;.;T;T;T;.
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;.;D;.;.;.;D;.;.;D;D
M_CAP	Benign	0.055	D
MetaRNN	Uncertain	0.67	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	1.8	L;L;L;L;L;.;L;.;L;L;L;L;.;L;L;L;.;L;L;L;.;L;L;L;.
PhyloP100		6.2
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.7	.;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.51
Sift	Uncertain	0.020	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.049	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Polyphen		0.031	B;B;B;B;B;.;B;.;B;B;B;B;.;B;B;B;.;B;B;B;.;B;B;B;.
Vest4		0.58
MutPred		0.62		Loss of catalytic residue at I405 (P = 0.1211);Loss of catalytic residue at I405 (P = 0.1211);Loss of catalytic residue at I405 (P = 0.1211);Loss of catalytic residue at I405 (P = 0.1211);Loss of catalytic residue at I405 (P = 0.1211);.;Loss of catalytic residue at I405 (P = 0.1211);.;Loss of catalytic residue at I405 (P = 0.1211);Loss of catalytic residue at I405 (P = 0.1211);Loss of catalytic residue at I405 (P = 0.1211);Loss of catalytic residue at I405 (P = 0.1211);.;Loss of catalytic residue at I405 (P = 0.1211);Loss of catalytic residue at I405 (P = 0.1211);Loss of catalytic residue at I405 (P = 0.1211);.;Loss of catalytic residue at I405 (P = 0.1211);Loss of catalytic residue at I405 (P = 0.1211);Loss of catalytic residue at I405 (P = 0.1211);.;Loss of catalytic residue at I405 (P = 0.1211);Loss of catalytic residue at I405 (P = 0.1211);Loss of catalytic residue at I405 (P = 0.1211);.;
MVP		0.74
MPC		1.2
ClinPred		0.90	D
GERP RS		5.6
Varity_R		0.55
gMVP		0.89
Mutation Taster		=55/45	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs759515813; hg19: chr3-11070928;