NM_003042.4:c.1255delC

Variant names:

• chr3-11029282-AC-A
• rs1553690583
• NM_003042.4:c.1255delC

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_003042.4(SLC6A1):​c.1255delC​(p.Arg419AlafsTer15) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC6A1 NM_003042.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: -0.192
• 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, Labcorp Genetics (formerly Invitae), PanelApp Australia, Illumina, G2P
• myoclonic-astatic epilepsy

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-11029282-AC-A is Pathogenic according to our data. Variant chr3-11029282-AC-A is described in ClinVar as Pathogenic. ClinVar VariationId is 475470.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A1	NM_003042.4	MANE Select	c.1255delC	p.Arg419AlafsTer15	frameshift	Exon 12 of 16	NP_003033.3
	SLC6A1	NM_001348250.2		c.1255delC	p.Arg419AlafsTer15	frameshift	Exon 12 of 16	NP_001335179.1	P30531
	SLC6A1	NM_001348251.2		c.895delC	p.Arg299AlafsTer15	frameshift	Exon 12 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.1255delC	p.Arg419AlafsTer15	frameshift	Exon 12 of 16	ENSP00000287766.4	P30531
	SLC6A1	ENST00000698198.1		c.1327delC	p.Arg443AlafsTer15	frameshift	Exon 10 of 14	ENSP00000513602.1	A0A8V8TMZ9
	SLC6A1	ENST00000644803.1		c.1282delC	p.Arg428AlafsTer15	frameshift	Exon 10 of 14	ENSP00000494469.1	A0A2R8YDD5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Epilepsy with myoclonic atonic seizures (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.19
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs1553690583; hg19: chr3-11070968;