3-11028856-GCC-GCCCC

Variant names:

• chr3-11028856-G-GCC
• rs3841958
• NM_003042.4:c.1191+16_1191+17dupCC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_003042.4(SLC6A1):​c.1191+16_1191+17dupCC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000979 in 1,571,924 control chromosomes in the GnomAD database, including 12 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0051 (8 hom., cov: 29)
  • Exomes 𝑓: 0.00054 (4 hom.)
• Consequence: SLC6A1 NM_003042.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.92
• 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, 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 -16 ACMG points.

• BP6: Variant 3-11028856-G-GCC is Benign according to our data. Variant chr3-11028856-G-GCC is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1167573.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00513 (776/151252) while in subpopulation AFR AF = 0.0178 (735/41202). AF 95% confidence interval is 0.0168. There are 8 homozygotes in GnomAd4. There are 383 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High AC in GnomAd4 at 776 AD,Unknown gene.

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.1191+16_1191+17dupCC		intron	N/A	NP_003033.3
	SLC6A1	NM_001348250.2		c.1191+16_1191+17dupCC		intron	N/A	NP_001335179.1	P30531
	SLC6A1	NM_001348251.2		c.831+16_831+17dupCC		intron	N/A	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.1191+16_1191+17dupCC		intron	N/A	ENSP00000287766.4	P30531
	SLC6A1	ENST00000698198.1		c.1263+16_1263+17dupCC		intron	N/A	ENSP00000513602.1	A0A8V8TMZ9
	SLC6A1	ENST00000644803.1		c.1191+16_1191+17dupCC		intron	N/A	ENSP00000494469.1	A0A2R8YDD5

Frequencies

GnomAD3 genomes AF: 0.00513 AC: 776 AN: 151134 Hom.: 8 Cov.: 29

Gnomad AFR AF: 0.0179

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00198

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000443

Gnomad OTH AF: 0.00338

GnomAD2 exomes AF: 0.00136 AC: 319 AN: 234778 AF XY: 0.00101

Gnomad AFR exome AF: 0.0185

Gnomad AMR exome AF: 0.000741

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000113

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000381

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000537 AC: 763 AN: 1420672 Hom.: 4 Cov.: 24 AF XY: 0.000461 AC XY: 327 AN XY: 709074

African (AFR) AF: 0.0198 AC: 640 AN: 32284

American (AMR) AF: 0.000765 AC: 34 AN: 44458

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25836

East Asian (EAS) AF: 0.000431 AC: 17 AN: 39416

South Asian (SAS) AF: 0.0000470 AC: 4 AN: 85056

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53000

Middle Eastern (MID) AF: 0.000360 AC: 2 AN: 5556

European-Non Finnish (NFE) AF: 0.0000112 AC: 12 AN: 1076126

Other (OTH) AF: 0.000916 AC: 54 AN: 58940

GnomAD4 genome AF: 0.00513 AC: 776 AN: 151252 Hom.: 8 Cov.: 29 AF XY: 0.00519 AC XY: 383 AN XY: 73864

African (AFR) AF: 0.0178 AC: 735 AN: 41202

American (AMR) AF: 0.00198 AC: 30 AN: 15180

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5116

South Asian (SAS) AF: 0.00 AC: 0 AN: 4776

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10452

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000443 AC: 3 AN: 67772

Other (OTH) AF: 0.00335 AC: 7 AN: 2092

Alfa AF: 0.000136 Hom.: 63

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Epilepsy with myoclonic atonic seizures (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.9
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3841958; hg19: chr3-11070542;