3-11022405-G-T

Variant names:

• chr3-11022405-G-T
• rs6344
• NM_003042.4:c.651G>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003042.4(SLC6A1):​c.651G>T​(p.Thr217Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0479 in 1,613,392 control chromosomes in the GnomAD database, including 2,298 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T217T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.041 (172 hom., cov: 33)
  • Exomes 𝑓: 0.049 (2126 hom.)
• Consequence: SLC6A1 NM_003042.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.33
• Publications: 10 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, Labcorp Genetics (formerly Invitae), PanelApp Australia, Illumina, G2P
• myoclonic-astatic epilepsy

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 3-11022405-G-T is Benign according to our data. Variant chr3-11022405-G-T is described in ClinVar as Benign. ClinVar VariationId is 448418.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.33 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.121 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A1	NM_003042.4	MANE Select	c.651G>T	p.Thr217Thr	synonymous	Exon 7 of 16	NP_003033.3
	SLC6A1	NM_001348250.2		c.651G>T	p.Thr217Thr	synonymous	Exon 7 of 16	NP_001335179.1	P30531
	SLC6A1	NM_001348251.2		c.291G>T	p.Thr97Thr	synonymous	Exon 7 of 16	NP_001335180.1	A0A2R8Y4I3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A1	ENST00000287766.10	TSL:1 MANE Select	c.651G>T	p.Thr217Thr	synonymous	Exon 7 of 16	ENSP00000287766.4	P30531
	SLC6A1	ENST00000698198.1		c.723G>T	p.Thr241Thr	synonymous	Exon 5 of 14	ENSP00000513602.1	A0A8V8TMZ9
	SLC6A1	ENST00000644803.1		c.651G>T	p.Thr217Thr	synonymous	Exon 5 of 14	ENSP00000494469.1	A0A2R8YDD5

Frequencies

GnomAD3 genomes AF: 0.0413 AC: 6279 AN: 152206 Hom.: 173 Cov.: 33

Gnomad AFR AF: 0.0304

Gnomad AMI AF: 0.0504

Gnomad AMR AF: 0.0308

Gnomad ASJ AF: 0.0599

Gnomad EAS AF: 0.0485

Gnomad SAS AF: 0.129

Gnomad FIN AF: 0.0312

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0438

Gnomad OTH AF: 0.0425

GnomAD2 exomes AF: 0.0509 AC: 12717 AN: 249628 AF XY: 0.0558

Gnomad AFR exome AF: 0.0308

Gnomad AMR exome AF: 0.0170

Gnomad ASJ exome AF: 0.0659

Gnomad EAS exome AF: 0.0434

Gnomad FIN exome AF: 0.0372

Gnomad NFE exome AF: 0.0462

Gnomad OTH exome AF: 0.0500

GnomAD4 exome AF: 0.0485 AC: 70931 AN: 1461068 Hom.: 2126 Cov.: 31 AF XY: 0.0512 AC XY: 37225 AN XY: 726752

African (AFR) AF: 0.0325 AC: 1086 AN: 33466

American (AMR) AF: 0.0189 AC: 842 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.0646 AC: 1686 AN: 26114

East Asian (EAS) AF: 0.0457 AC: 1813 AN: 39672

South Asian (SAS) AF: 0.126 AC: 10818 AN: 86054

European-Finnish (FIN) AF: 0.0383 AC: 2045 AN: 53364

Middle Eastern (MID) AF: 0.0688 AC: 396 AN: 5760

European-Non Finnish (NFE) AF: 0.0442 AC: 49170 AN: 1111632

Other (OTH) AF: 0.0510 AC: 3075 AN: 60348

GnomAD4 genome AF: 0.0412 AC: 6278 AN: 152324 Hom.: 172 Cov.: 33 AF XY: 0.0418 AC XY: 3116 AN XY: 74482

African (AFR) AF: 0.0304 AC: 1264 AN: 41582

American (AMR) AF: 0.0307 AC: 470 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0599 AC: 208 AN: 3472

East Asian (EAS) AF: 0.0479 AC: 248 AN: 5180

South Asian (SAS) AF: 0.129 AC: 622 AN: 4820

European-Finnish (FIN) AF: 0.0312 AC: 331 AN: 10616

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0438 AC: 2982 AN: 68028

Other (OTH) AF: 0.0421 AC: 89 AN: 2116

Alfa AF: 0.0444 Hom.: 225

Bravo AF: 0.0397

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Epilepsy with myoclonic atonic seizures (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	6.2
DANN	Benign	0.83
PhyloP100		-2.3
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs6344; hg19: chr3-11064091; COSMIC: COSV55117582; COSMIC: COSV55117582;