11-20604316-C-T
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_004211.5(SLC6A5):c.571C>T(p.Arg191Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000508 in 1,613,472 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. R191R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_004211.5 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC6A5 | NM_004211.5 | c.571C>T | p.Arg191Ter | stop_gained | 3/16 | ENST00000525748.6 | |
SLC6A5 | NM_001318369.2 | c.-24+2651C>T | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC6A5 | ENST00000525748.6 | c.571C>T | p.Arg191Ter | stop_gained | 3/16 | 1 | NM_004211.5 | P1 | |
SLC6A5 | ENST00000298923.11 | c.540+2651C>T | intron_variant, NMD_transcript_variant | 1 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152088Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 250650Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135452
GnomAD4 exome AF: 0.0000554 AC: 81AN: 1461384Hom.: 0 Cov.: 31 AF XY: 0.0000495 AC XY: 36AN XY: 726982
GnomAD4 genome AF: 0.00000658 AC: 1AN: 152088Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74278
ClinVar
Submissions by phenotype
Hyperekplexia 3 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 02, 2023 | This sequence change creates a premature translational stop signal (p.Arg191*) in the SLC6A5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC6A5 are known to be pathogenic (PMID: 14622583, 16751771, 22700964). This variant is present in population databases (rs376783257, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with hyperekplexia (PMID: 22700964). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 579017). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at