3-11017216-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP6_Moderate

The NM_003042.4(SLC6A1):c.5C>T(p.Ala2Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,250 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2E) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SLC6A1 NM_003042.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.52

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-AS1 (HGNC:40546): (SLC6A1 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SLC6A1
• BP6: Variant 3-11017216-C-T is Benign according to our data. Variant chr3-11017216-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2155429.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC6A1	NM_003042.4	c.5C>T	p.Ala2Val	missense_variant	3/16	ENST00000287766.10
SLC6A1-AS1	NR_046647.1	n.105+1904G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC6A1	ENST00000287766.10	c.5C>T	p.Ala2Val	missense_variant	3/16	1	NM_003042.4	P1
SLC6A1-AS1	ENST00000414969.2	n.105+1904G>A		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461250 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726844

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Myoclonic-atonic epilepsy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Aug 16, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Uncertain	0.070	D
BayesDel_noAF	Benign	-0.14
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.27	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.;T;.;T;T;.;.;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Benign	0.038	D
MetaRNN	Uncertain	0.47	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	0.97	L;L;L;L;L;L;L;L;L;L;L;L;L;L;L;L;.;L;.;L;L;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.71	T
Polyphen		0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.;D;.;D;D;.;.;.
Vest4		0.63
MutPred		0.20		Gain of MoRF binding (P = 0.0994);Gain of MoRF binding (P = 0.0994);Gain of MoRF binding (P = 0.0994);Gain of MoRF binding (P = 0.0994);Gain of MoRF binding (P = 0.0994);Gain of MoRF binding (P = 0.0994);Gain of MoRF binding (P = 0.0994);Gain of MoRF binding (P = 0.0994);Gain of MoRF binding (P = 0.0994);Gain of MoRF binding (P = 0.0994);Gain of MoRF binding (P = 0.0994);Gain of MoRF binding (P = 0.0994);Gain of MoRF binding (P = 0.0994);Gain of MoRF binding (P = 0.0994);Gain of MoRF binding (P = 0.0994);Gain of MoRF binding (P = 0.0994);Gain of MoRF binding (P = 0.0994);Gain of MoRF binding (P = 0.0994);Gain of MoRF binding (P = 0.0994);Gain of MoRF binding (P = 0.0994);Gain of MoRF binding (P = 0.0994);Gain of MoRF binding (P = 0.0994);Gain of MoRF binding (P = 0.0994);Gain of MoRF binding (P = 0.0994);
MVP		0.67
MPC		1.8
ClinPred		0.92	D
GERP RS		4.4
Varity_R		0.10
gMVP		0.66

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

Publications

LitVar

Other links and lift over

dbSNP: rs913073947; hg19: chr3-11058902;