rs777641484
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5
The NM_000441.2(SLC26A4):c.2005G>A(p.Asp669Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,536 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D669E) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000441.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC26A4 | NM_000441.2 | c.2005G>A | p.Asp669Asn | missense_variant | 17/21 | ENST00000644269.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC26A4 | ENST00000644269.2 | c.2005G>A | p.Asp669Asn | missense_variant | 17/21 | NM_000441.2 | P1 | ||
SLC26A4 | ENST00000492030.2 | n.292G>A | non_coding_transcript_exon_variant | 2/6 | 5 | ||||
SLC26A4 | ENST00000644846.1 | c.718G>A | p.Asp240Asn | missense_variant, NMD_transcript_variant | 7/10 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152186Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251198Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135754
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461350Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727036
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152186Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74342
ClinVar
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 25, 2022 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 04, 2022 | For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SLC26A4 protein function. ClinVar contains an entry for this variant (Variation ID: 554553). This missense change has been observed in individual(s) with Pendred syndrome (PMID: 15611902, 20601923). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs777641484, gnomAD 0.003%). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 669 of the SLC26A4 protein (p.Asp669Asn). - |
Pendred syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Oct 26, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at