NM_052867.4:c.5156G>A

Variant names:

• chr13-101055356-C-T
• rs2031082481
• NM_052867.4:c.5156G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_052867.4(NALCN):​c.5156G>A​(p.Trp1719*) variant causes a stop gained 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NALCN NM_052867.4 stop_gained
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57
• Publications: 0 publications found

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]

NALCN-AS1 (HGNC:42743): (NALCN antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0117 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_052867.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NALCN	NM_052867.4	MANE Select	c.5156G>A	p.Trp1719*	stop_gained	Exon 44 of 44	NP_443099.1	Q8IZF0-1
	NALCN	NM_001350748.2		c.5243G>A	p.Trp1748*	stop_gained	Exon 45 of 45	NP_001337677.1	A0A6Q8PFS9
	NALCN	NM_001350749.2		c.5156G>A	p.Trp1719*	stop_gained	Exon 44 of 44	NP_001337678.1	Q8IZF0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NALCN	ENST00000251127.11	TSL:1 MANE Select	c.5156G>A	p.Trp1719*	stop_gained	Exon 44 of 44	ENSP00000251127.6	Q8IZF0-1
	NALCN	ENST00000675332.1		c.5243G>A	p.Trp1748*	stop_gained	Exon 45 of 45	ENSP00000501955.1	A0A6Q8PFS9
	NALCN	ENST00000858715.1		c.5156G>A	p.Trp1719*	stop_gained	Exon 44 of 44	ENSP00000528774.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	46
DANN	Uncertain	1.0
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		7.6
Vest4		0.78
GERP RS		5.4
Mutation Taster		=11/189	disease causing

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

Other links and lift over

dbSNP: rs2031082481; hg19: chr13-101707708;