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

Genomes: not found (cov: 32)

Consequence

NALCN
NM_052867.4 missense

Scores

17
1
1

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 8.74
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr13-101103179-A-G is described in Lovd as [Pathogenic].
PP2
Missense variant in the NALCN gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 63 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Gene score misZ: 4.9555 (above the threshold of 3.09). Trascript score misZ: 6.7536 (above the threshold of 3.09). GenCC associations: The gene is linked to hypotonia, infantile, with psychomotor retardation and characteristic facies 1, digitotalar dysmorphism, hypotonia, infantile, with psychomotor retardation and characteristic facies, congenital contractures of the limbs and face, hypotonia, and developmental delay, Freeman-Sheldon syndrome, Sheldon-hall syndrome.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.981
PP5
Variant 13-101103179-A-C is Pathogenic according to our data. Variant chr13-101103179-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1708474.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NALCNNM_052867.4 linkc.3050T>G p.Ile1017Ser missense_variant Exon 26 of 44 ENST00000251127.11 NP_443099.1 Q8IZF0-1A0A024RE05

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NALCNENST00000251127.11 linkc.3050T>G p.Ile1017Ser missense_variant Exon 26 of 44 1 NM_052867.4 ENSP00000251127.6 Q8IZF0-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

NALCN-related disorder Pathogenic:1
Jan 26, 2024
PreventionGenetics, part of Exact Sciences
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

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
Sep 30, 2022
Genomics Laboratory, Royal University Hospital
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Pathogenic
0.57
D
BayesDel_noAF
Pathogenic
0.58
CADD
Pathogenic
26
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.97
D
Eigen
Pathogenic
0.91
Eigen_PC
Pathogenic
0.79
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
1.0
D
M_CAP
Pathogenic
0.83
D
MetaRNN
Pathogenic
0.98
D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.9
H
PrimateAI
Pathogenic
0.88
D
PROVEAN
Pathogenic
-5.1
D
REVEL
Pathogenic
0.99
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.99
MutPred
0.74
Gain of catalytic residue at S1021 (P = 9e-04);
MVP
0.74
MPC
1.2
ClinPred
1.0
D
GERP RS
5.0
Varity_R
0.96
gMVP
0.97

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-101755530; API