rs878853127

Positions:

• chr13-101068026-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

The NM_052867.4(NALCN):​c.4338T>G​(p.Ile1446Met) variant causes a missense change involving the alteration of a non-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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: NALCN NM_052867.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.52

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 Likely_pathogenic. Variant got 6 ACMG points.

• 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, 0.918
• PP5: Variant 13-101068026-A-C is Pathogenic according to our data. Variant chr13-101068026-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 235830.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NALCN	NM_052867.4	c.4338T>G	p.Ile1446Met	missense_variant	39/44	ENST00000251127.11	NP_443099.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NALCN	ENST00000251127.11	c.4338T>G	p.Ile1446Met	missense_variant	39/44	1	NM_052867.4	ENSP00000251127	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Congenital contractures of the limbs and face, hypotonia, and developmental delay Pathogenic:1

Pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

May 19, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.81	D
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.4	N
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.99	D
Vest4		0.98
MutPred		0.61		Gain of catalytic residue at L1442 (P = 0.0019);
MVP		0.71
MPC		2.5
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.91
gMVP		0.98

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

LitVar

Other links and lift over

dbSNP: rs878853127; hg19: chr13-101720378;