rs582504

chr13-101060982-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_052867.4(NALCN):c.4755+986C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.129 in 152,138 control chromosomes in the GnomAD database, including 2,124 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.13 (2124 hom., cov: 32)
• Consequence: NALCN NM_052867.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.877

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.293 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NALCN	NM_052867.4	c.4755+986C>A		intron_variant		ENST00000251127.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NALCN	ENST00000251127.11	c.4755+986C>A		intron_variant		1	NM_052867.4	P1

Frequencies

GnomAD3 genomes AF: 0.129 AC: 19555 AN: 152020 Hom.: 2119 Cov.: 32

Gnomad AFR AF: 0.297

Gnomad AMI AF: 0.0406

Gnomad AMR AF: 0.0816

Gnomad ASJ AF: 0.104

Gnomad EAS AF: 0.0352

Gnomad SAS AF: 0.110

Gnomad FIN AF: 0.0383

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.0624

Gnomad OTH AF: 0.108

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.129 AC: 19591 AN: 152138 Hom.: 2124 Cov.: 32 AF XY: 0.126 AC XY: 9384 AN XY: 74356

Gnomad4 AFR AF: 0.297

Gnomad4 AMR AF: 0.0814

Gnomad4 ASJ AF: 0.104

Gnomad4 EAS AF: 0.0355

Gnomad4 SAS AF: 0.110

Gnomad4 FIN AF: 0.0383

Gnomad4 NFE AF: 0.0624

Gnomad4 OTH AF: 0.107

Alfa AF: 0.0833 Hom.: 362

Bravo AF: 0.137

Asia WGS AF: 0.0850 AC: 293 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	6.2
Dann	Benign	0.65

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: rs582504; hg19: chr13-101713334;