chr3-11034650-C-T

Variant names:

• chr3-11034650-C-T
• rs2272401
• NM_003042.4:c.1647C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_003042.4(SLC6A1):​c.1647C>T​(p.Pro549Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00152 in 1,614,070 control chromosomes in the GnomAD database, including 26 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. P549P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0019 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (24 hom.)
• Consequence: SLC6A1 NM_003042.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -3.32
• Publications: 2 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 3-11034650-C-T is Benign according to our data. Variant chr3-11034650-C-T is described in ClinVar as Benign. ClinVar VariationId is 475475.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.32 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00185 (282/152302) while in subpopulation EAS AF = 0.0371 (192/5178). AF 95% confidence interval is 0.0328. There are 2 homozygotes in GnomAd4. There are 162 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 282 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A1	NM_003042.4	MANE Select	c.1647C>T	p.Pro549Pro	synonymous	Exon 15 of 16	NP_003033.3
	SLC6A1	NM_001348250.2		c.1647C>T	p.Pro549Pro	synonymous	Exon 15 of 16	NP_001335179.1
	SLC6A1	NM_001348251.2		c.1287C>T	p.Pro429Pro	synonymous	Exon 15 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.1647C>T	p.Pro549Pro	synonymous	Exon 15 of 16	ENSP00000287766.4
	SLC6A1	ENST00000698198.1		c.1719C>T	p.Pro573Pro	synonymous	Exon 13 of 14	ENSP00000513602.1
	SLC6A1	ENST00000644803.1		c.1674C>T	p.Pro558Pro	synonymous	Exon 13 of 14	ENSP00000494469.1

Frequencies

GnomAD3 genomes AF: 0.00185 AC: 282 AN: 152184 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.0370

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.00367

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00376 AC: 945 AN: 251394 AF XY: 0.00358

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00248

Gnomad EAS exome AF: 0.0398

Gnomad FIN exome AF: 0.00383

Gnomad NFE exome AF: 0.000264

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.00148 AC: 2164 AN: 1461768 Hom.: 24 Cov.: 33 AF XY: 0.00150 AC XY: 1088 AN XY: 727198

African (AFR) AF: 0.0000597 AC: 2 AN: 33478

American (AMR) AF: 0.000246 AC: 11 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00226 AC: 59 AN: 26136

East Asian (EAS) AF: 0.0362 AC: 1438 AN: 39700

South Asian (SAS) AF: 0.00181 AC: 156 AN: 86254

European-Finnish (FIN) AF: 0.00373 AC: 199 AN: 53418

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.000149 AC: 166 AN: 1111898

Other (OTH) AF: 0.00215 AC: 130 AN: 60394

GnomAD4 genome AF: 0.00185 AC: 282 AN: 152302 Hom.: 2 Cov.: 32 AF XY: 0.00218 AC XY: 162 AN XY: 74482

African (AFR) AF: 0.00 AC: 0 AN: 41562

American (AMR) AF: 0.000196 AC: 3 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.0371 AC: 192 AN: 5178

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4824

European-Finnish (FIN) AF: 0.00367 AC: 39 AN: 10620

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

European-Non Finnish (NFE) AF: 0.000426 AC: 29 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000437 Hom.: 0

Bravo AF: 0.00189

Asia WGS AF: 0.0130 AC: 47 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

ClinVar submissions as Germline

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)
-	-	1	SLC6A1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	1.0
DANN	Benign	0.59
PhyloP100		-3.3
Mutation Taster		=97/3	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: rs2272401; hg19: chr3-11076336; COSMIC: COSV55115761; COSMIC: COSV55115761;