rs754749693

Variant names:

• chr3-11022412-A-G
• rs754749693
• NM_003042.4:c.658A>G

Your query was ambiguous. Multiple possible variants found:

• chr3-11022412-A-G
• chr3-11022412-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PM1 PM2 BP4_Moderate BP6_Moderate

The NM_003042.4(SLC6A1):​c.658A>G​(p.Ile220Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,078 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. I220I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SLC6A1 NM_003042.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.02
• Publications: 1 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 0 ACMG points.

• PM1: In a hotspot region, there are 3 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.23630688).
• BP6: Variant 3-11022412-A-G is Benign according to our data. Variant chr3-11022412-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 573328.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003042.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A1	NM_003042.4	MANE Select	c.658A>G	p.Ile220Val	missense	Exon 7 of 16	NP_003033.3
	SLC6A1	NM_001348250.2		c.658A>G	p.Ile220Val	missense	Exon 7 of 16	NP_001335179.1
	SLC6A1	NM_001348251.2		c.298A>G	p.Ile100Val	missense	Exon 7 of 16	NP_001335180.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A1	ENST00000287766.10	TSL:1 MANE Select	c.658A>G	p.Ile220Val	missense	Exon 7 of 16	ENSP00000287766.4
	SLC6A1	ENST00000698198.1		c.730A>G	p.Ile244Val	missense	Exon 5 of 14	ENSP00000513602.1
	SLC6A1	ENST00000644803.1		c.658A>G	p.Ile220Val	missense	Exon 5 of 14	ENSP00000494469.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000803 AC: 2 AN: 249202 AF XY: 0.00000743

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000581

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461078 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726714

African (AFR) AF: 0.00 AC: 0 AN: 33454

American (AMR) AF: 0.0000672 AC: 3 AN: 44654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 85978

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111704

Other (OTH) AF: 0.0000166 AC: 1 AN: 60368

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Epilepsy with myoclonic atonic seizures (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.19
Eigen_PC	Benign	0.040
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.0087	T
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.17	N
PhyloP100		4.0
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.19
Sift	Benign	0.18	T
Sift4G	Benign	0.29	T
Polyphen		0.0080	B
Vest4		0.51
MutPred		0.54		Gain of catalytic residue at I220 (P = 0.1569)
MVP		0.54
MPC		0.88
ClinPred		0.42	T
GERP RS		5.0
Varity_R		0.12
gMVP		0.60
Mutation Taster		=68/32	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: rs754749693; hg19: chr3-11064098;