rs79264337
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The ENST00000251127.11(NALCN):c.2241C>T(p.Pro747=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00371 in 1,608,526 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0049 ( 2 hom., cov: 32)
Exomes 𝑓: 0.0036 ( 10 hom. )
Consequence
NALCN
ENST00000251127.11 synonymous
ENST00000251127.11 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -4.83
Genes affected
NALCN (HGNC:19082): (sodium leak channel, non-selective) This gene encodes a voltage-independent, nonselective cation channel which belongs to a family of voltage-gated sodium and calcium channels that regulates the resting membrane potential and excitability of neurons. This family is expressed throughout the nervous system and conducts a persistent sodium leak current that contributes to tonic neuronal excitability. The encoded protein forms a channelosome complex that includes G-protein-coupled receptors, UNC-79, UNC-80, NCA localization factor-1, and src family tyrosine kinases. Naturally occurring mutations in this gene are associated with infantile neuroaxonal dystrophy, infantile hypotonia with psychomotor retardation and characteristic facies (IHPRF) syndrome, and congenital contractures of the limbs and face with hypotonia and developmental delay (CLIFAHDD) syndrome. A knockout of the orthologous gene in mice results in paralysis with a severely disrupted respiratory rhythm, and lethality within 24 hours after birth. [provided by RefSeq, Apr 2017]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -21 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.75).
BP6
Variant 13-101111178-G-A is Benign according to our data. Variant chr13-101111178-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 262254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-101111178-G-A is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=-4.83 with no splicing effect.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00494 (751/152164) while in subpopulation AFR AF= 0.0104 (430/41518). AF 95% confidence interval is 0.00955. There are 2 homozygotes in gnomad4. There are 340 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 2 AD,AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NALCN | NM_052867.4 | c.2241C>T | p.Pro747= | synonymous_variant | 19/44 | ENST00000251127.11 | NP_443099.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NALCN | ENST00000251127.11 | c.2241C>T | p.Pro747= | synonymous_variant | 19/44 | 1 | NM_052867.4 | ENSP00000251127 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00493 AC: 750AN: 152046Hom.: 2 Cov.: 32
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GnomAD3 exomes AF: 0.00277 AC: 693AN: 250570Hom.: 1 AF XY: 0.00272 AC XY: 368AN XY: 135466
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GnomAD4 exome AF: 0.00359 AC: 5223AN: 1456362Hom.: 10 Cov.: 31 AF XY: 0.00340 AC XY: 2463AN XY: 723538
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GnomAD4 genome AF: 0.00494 AC: 751AN: 152164Hom.: 2 Cov.: 32 AF XY: 0.00457 AC XY: 340AN XY: 74384
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:4
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 19, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | NALCN: BP4, BP7, BS1, BS2 - |
Likely benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Sep 05, 2018 | - - |
NALCN-related disorder Benign:1
Benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 05, 2019 | This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Hypotonia, infantile, with psychomotor retardation and characteristic facies 1;C4225398:Congenital contractures of the limbs and face, hypotonia, and developmental delay Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 22, 2021 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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