rs150794709
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_006172.4(NPPA):c.197C>T(p.Pro66Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00027 in 1,613,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P66P) has been classified as Benign.
Frequency
Consequence
NM_006172.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NPPA | NM_006172.4 | c.197C>T | p.Pro66Leu | missense_variant | 2/3 | ENST00000376480.7 | NP_006163.1 | |
NPPA-AS1 | NR_037806.1 | n.1480-68G>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NPPA | ENST00000376480.7 | c.197C>T | p.Pro66Leu | missense_variant | 2/3 | 1 | NM_006172.4 | ENSP00000365663 | P1 | |
CLCN6 | ENST00000446542.5 | n.782-68G>A | intron_variant, non_coding_transcript_variant | 1 | ||||||
NPPA | ENST00000376476.1 | c.47C>T | p.Pro16Leu | missense_variant | 2/3 | 3 | ENSP00000365659 | |||
CLCN6 | ENST00000400892.3 | c.*1962-211G>A | intron_variant, NMD_transcript_variant | 3 | ENSP00000496938 |
Frequencies
GnomAD3 genomes AF: 0.000112 AC: 17AN: 152186Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000801 AC: 20AN: 249666Hom.: 0 AF XY: 0.0000665 AC XY: 9AN XY: 135262
GnomAD4 exome AF: 0.000286 AC: 418AN: 1461592Hom.: 0 Cov.: 32 AF XY: 0.000298 AC XY: 217AN XY: 727092
GnomAD4 genome AF: 0.000112 AC: 17AN: 152186Hom.: 0 Cov.: 32 AF XY: 0.0000941 AC XY: 7AN XY: 74354
ClinVar
Submissions by phenotype
Atrial fibrillation, familial, 6;C3810401:Atrial standstill 2 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 21, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Mar 30, 2021 | NPPA NM_006172.3 exon 2 p.Pro66Leu (c.197C>T): This variant has not been reported in the literature and is present in 0.01% (20/127896) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/1-11907423-G-A). This variant is present in ClinVar (Variation ID:469605). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 15, 2021 | The c.197C>T (p.P66L) alteration is located in exon 2 (coding exon 2) of the NPPA gene. This alteration results from a C to T substitution at nucleotide position 197, causing the proline (P) at amino acid position 66 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Atrial fibrillation, familial, 6 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 07, 2023 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 66 of the NPPA protein (p.Pro66Leu). This variant is present in population databases (rs150794709, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with NPPA-related conditions. ClinVar contains an entry for this variant (Variation ID: 469605). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at