rs376152742
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_052867.4(NALCN):c.2563C>T(p.Arg855*) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000254 in 1,613,976 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 (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_052867.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NALCN | NM_052867.4 | c.2563C>T | p.Arg855* | stop_gained | Exon 22 of 44 | ENST00000251127.11 | NP_443099.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152212Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251272Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135796
GnomAD4 exome AF: 0.0000267 AC: 39AN: 1461764Hom.: 0 Cov.: 31 AF XY: 0.0000316 AC XY: 23AN XY: 727178
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152212Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74346
ClinVar
Submissions by phenotype
Hypotonia, infantile, with psychomotor retardation and characteristic facies 1 Pathogenic:3
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The stop gained variant has been reported previously in homozygous and compound heterozygous state in patients affected with Infantile hypotonia with psychomotor retardation and characteristic facies (Karimi et al). The c.2563C>T variant is reported with the allele frequency of 0.002123% in gnomAD and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic. The nucleotide change c.2563C>T in NALCN is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. -
The WES analysis identified a stop gain mutation in the NALCN gene on chromosome13 (NM_052867); chr13:101107503G/A c.2563C>T p.R855X (rs376152742). The mutation was predicted to be pathogenic by MutationTaster and CADD_phred. Our review of the public resources, local population database, and the literature revealed that there is no previous publication describing this mutation in homozygous form. However, a single ClinVar submission confirmed the pathogenic effects of this genetic anomaly but merely provided an overview of the resulting manifestations with no detailed information. Furthermore, it failed to distinguish between IHPRF1 and CLIFAHDD and resulted in confusion by referring to several publications on CLIFAHDD as supporting evidence (SCV000742166.1). Sanger sequencing confirmed the presence of the mutation and its homozygosity in the proband and segregated with the autosomal recessive inheritance pattern of IHPRF1 in all tested individuals. -
Inborn genetic diseases Pathogenic:1
The alteration results in a premature stop codon: _x000D_ _x000D_ The c.2563C>T (p.R855*) alteration, located in exon 22 (coding exon 21) of the NALCN gene, results from a C to T substitution at nucleotide position 2563. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 855. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. The alteration has been observed in an affected individual: _x000D_ _x000D_ This alteration was reported in a patient with developmental delay, hypotonia, feeding difficulties, plagiocephaly, and disordered respiratory rhythm with central apnea (Campbell, 2018). Based on the available evidence, this alteration is classified as pathogenic. -
not provided Pathogenic:1
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 29610177, 32943903, 35808948) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at