rs2044117

chr13-101055958-G-A

Variant summary

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

The NM_052867.4(NALCN):c.5024-470C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.186 in 152,136 control chromosomes in the GnomAD database, including 2,839 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 0.19 (2839 hom., cov: 32)
• Consequence: NALCN NM_052867.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.199

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.231 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NALCN	NM_052867.4	c.5024-470C>T		intron_variant		ENST00000251127.11
NALCN-AS1	NR_047687.1	n.770+512G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NALCN	ENST00000251127.11	c.5024-470C>T		intron_variant		1	NM_052867.4	P1
NALCN-AS1	ENST00000457843.1	n.770+512G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.186 AC: 28269 AN: 152018 Hom.: 2839 Cov.: 32

Gnomad AFR AF: 0.156

Gnomad AMI AF: 0.156

Gnomad AMR AF: 0.137

Gnomad ASJ AF: 0.181

Gnomad EAS AF: 0.00598

Gnomad SAS AF: 0.122

Gnomad FIN AF: 0.188

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.234

Gnomad OTH AF: 0.186

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

GnomAD4 genome AF: 0.186 AC: 28276 AN: 152136 Hom.: 2839 Cov.: 32 AF XY: 0.180 AC XY: 13402 AN XY: 74374

Gnomad4 AFR AF: 0.156

Gnomad4 AMR AF: 0.137

Gnomad4 ASJ AF: 0.181

Gnomad4 EAS AF: 0.00599

Gnomad4 SAS AF: 0.121

Gnomad4 FIN AF: 0.188

Gnomad4 NFE AF: 0.234

Gnomad4 OTH AF: 0.185

Alfa AF: 0.212 Hom.: 6570

Bravo AF: 0.179

Asia WGS AF: 0.0840 AC: 295 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	1.3
Dann	Benign	0.56

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: rs2044117; hg19: chr13-101708310;