rs786201003

Positions:

• chr13-101083752-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP2 PP3 PP5_Very_Strong

The NM_052867.4(NALCN):​c.3542G>A​(p.Arg1181Gln) 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. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NALCN NM_052867.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 7.48

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a helix (size 14) in uniprot entity NALCN_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_052867.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NALCN. . Gene score misZ 4.9555 (greater than the threshold 3.09). Trascript score misZ 6.7536 (greater than threshold 3.09). GenCC has associacion of gene with 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, 0.749
• PP5: Variant 13-101083752-C-T is Pathogenic according to our data. Variant chr13-101083752-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188046.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-101083752-C-T is described in Lovd as [Pathogenic]. Variant chr13-101083752-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NALCN	NM_052867.4	c.3542G>A	p.Arg1181Gln	missense_variant	31/44	ENST00000251127.11	NP_443099.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NALCN	ENST00000251127.11	c.3542G>A	p.Arg1181Gln	missense_variant	31/44	1	NM_052867.4	ENSP00000251127	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461564 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727056

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 13, 2022	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33060286, 28454995, 34370008, 35256540, 31409833, 25864427, 25683120, 26763878) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Sep 15, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 14, 2022	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 188046). This missense change has been observed in individual(s) with arthrogryposis/congenital contractures, ataxia, developmental delay, facial dysmorphism, and/or hypotonia (PMID: 25683120, 25864427, 26763878). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1181 of the NALCN protein (p.Arg1181Gln). -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2022	NALCN: PS2, PM2, PS4:Moderate, PP2, PP3, PS3:Supporting -

Congenital contractures of the limbs and face, hypotonia, and developmental delay Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Nov 07, 2022	- -
Pathogenic, no assertion criteria provided	research	University of Washington Center for Mendelian Genomics, University of Washington	May 19, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	Jan 13, 2016	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 19, 2018

- -

Intellectual disability with episodic ataxia and congenital arthrogryposis Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

CHU Sainte-Justine Research Center, University of Montreal

Jan 01, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.69	D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.9	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0030	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.69	P
Vest4		0.75
MutPred		0.45		Loss of MoRF binding (P = 0.0403);
MVP		0.70
MPC		1.8
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.77
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs786201003; hg19: chr13-101736103;