rs5065
Positions:
Variant summary
Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM4BP6_Very_StrongBA1
The NM_006172.4(NPPA):āc.454T>Cā(p.Ter152ArgextTer2) variant causes a stop lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.153 in 1,613,250 control chromosomes in the GnomAD database, including 22,231 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (ā ā ).
Frequency
Genomes: š 0.21 ( 4472 hom., cov: 32)
Exomes š: 0.15 ( 17759 hom. )
Consequence
NPPA
NM_006172.4 stop_lost
NM_006172.4 stop_lost
Scores
1
6
Clinical Significance
Conservation
PhyloP100: 0.328
Genes affected
NPPA (HGNC:7939): (natriuretic peptide A) The protein encoded by this gene belongs to the natriuretic peptide family. Natriuretic peptides are implicated in the control of extracellular fluid volume and electrolyte homeostasis. This protein is synthesized as a large precursor (containing a signal peptide), which is processed to release a peptide from the N-terminus with similarity to vasoactive peptide, cardiodilatin, and another peptide from the C-terminus with natriuretic-diuretic activity. Mutations in this gene have been associated with atrial fibrillation familial type 6. This gene is located adjacent to another member of the natriuretic family of peptides on chromosome 1. [provided by RefSeq, Oct 2015]
CLCN6 (HGNC:2024): (chloride voltage-gated channel 6) This gene encodes a member of the voltage-dependent chloride channel protein family. Members of this family can function as either chloride channels or antiporters. This protein is primarily localized to late endosomes and functions as a chloride/proton antiporter. Alternate splicing results in both coding and non-coding variants. Additional alternately spliced variants have been described but their full-length structure is unknown. [provided by RefSeq, Mar 2012]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -14 ACMG points.
PM4
?
Stoplost variant in NM_006172.4 Downstream stopcodon found after 1 codons.
BP6
?
Variant 1-11846011-A-G is Benign according to our data. Variant chr1-11846011-A-G is described in ClinVar as [Benign]. Clinvar id is 226855.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-11846011-A-G is described in Lovd as [Benign].
BA1
?
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.398 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NPPA | NM_006172.4 | c.454T>C | p.Ter152ArgextTer2 | stop_lost | 3/3 | ENST00000376480.7 | |
NPPA-AS1 | NR_037806.1 | n.1479+245A>G | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NPPA | ENST00000376480.7 | c.454T>C | p.Ter152ArgextTer2 | stop_lost | 3/3 | 1 | NM_006172.4 | P1 | |
CLCN6 | ENST00000446542.5 | n.781+245A>G | intron_variant, non_coding_transcript_variant | 1 | |||||
NPPA | ENST00000376476.1 | c.304T>C | p.Ter102ArgextTer2 | stop_lost | 3/3 | 3 | |||
CLCN6 | ENST00000400892.3 | c.*1961+245A>G | intron_variant, NMD_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.207 AC: 31395AN: 151958Hom.: 4465 Cov.: 32
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GnomAD3 exomes AF: 0.137 AC: 34498AN: 250974Hom.: 3300 AF XY: 0.136 AC XY: 18436AN XY: 135722
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GnomAD4 exome AF: 0.147 AC: 214793AN: 1461174Hom.: 17759 Cov.: 31 AF XY: 0.147 AC XY: 107035AN XY: 726952
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GnomAD4 genome ? AF: 0.207 AC: 31425AN: 152076Hom.: 4472 Cov.: 32 AF XY: 0.203 AC XY: 15105AN XY: 74346
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568
ALSPAC
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533
ESP6500AA
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1800
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1335
ExAC
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17445
Asia WGS
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ClinVar
Significance: Benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 31, 2015 | p.X152ArgextX3 in exon 3 of NPPA: This variant is not expected to have clinical significance since it has been identified in 40.1% (4244/10406) of African chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs5065). - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 12, 2016 | - - |
Atrial fibrillation, familial, 6 Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | GeneDx | Nov 15, 2018 | This variant is associated with the following publications: (PMID: 23529183, 22400494, 20543198, 17984371, 24041948, 19702001, 22575314, 25401746, 15017020, 29439446) - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Benign
N
MutationTaster
Benign
P;P
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at