rs878853129
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PM5PP2PP3_StrongPP5_Moderate
The NM_052867.4(NALCN):c.3050T>G(p.Ile1017Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1017T) has been classified as Pathogenic.
Frequency
Consequence
NM_052867.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NALCN | NM_052867.4 | c.3050T>G | p.Ile1017Ser | missense_variant | Exon 26 of 44 | ENST00000251127.11 | NP_443099.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
NALCN-related disorder Pathogenic:1
The NALCN c.3050T>G variant is predicted to result in the amino acid substitution p.Ile1017Ser. This variant was reported in a patient with features of autosomal dominant congenital contractures of the limbs and face, hypotonia, and developmental delay (CLIFAHDD) syndrome (Hashemi B. et al. 2023. PubMed ID: 37469362). A different amino acid substitution at this position (c.3050T>C, p.Ile1017Thr) has been reported to occur de novo in a patient with features of CLIFAHDD syndrome (Chong et al 2015. PubMed ID: 25683120). Functional studies on the p.Ile1017Thr variant suggest this residue may be important for protein function (ExtData Figure 10c in Kschonsak M et al 2020. PubMed ID: 32698188). To our knowledge, this variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Taken together, we interpret this variant as likely pathogenic. -
Congenital contractures of the limbs and face, hypotonia, and developmental delay Pathogenic:1
The Ile1017Ser variant in NALCN has not been reported in the literature or in gnomAD database. In silico analysis predicts this variant is probably damaging by Polyphen2, SIFT and Mutation Taster. Multiple sequence alignment reveals that Ile1017 are highly conserved among animals, and also conserved for being hydrophobic in fungal and plant species. Another missense variant at the same amnio acid, Ile1017Thr, has been reported in individuals with CLIFAHDD syndrome (PMID: 25683120). Experimental studies on Ile1017Thr reveal that the switch of the property from hydrophobic to polar resulting in a gain-of-function phenotypes (PMID: 32698188). Given the comparable property change introduced by Ile1017Thr and the newly identified Ile1017Ser, we interpret the Ile1017Ser variant as likely pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.