rs1538240

Variant names:

• chr13-101315959-T-C
• rs1538240
• NM_052867.4:c.800-23593A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_052867.4(NALCN):​c.800-23593A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.471 in 151,810 control chromosomes in the GnomAD database, including 17,191 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 0.47 (17191 hom., cov: 30)
• Consequence: NALCN NM_052867.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0890
• Publications: 2 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 Gene-Disease associations (from GenCC):

• congenital contractures of the limbs and face, hypotonia, and developmental delay

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• hypotonia, infantile, with psychomotor retardation and characteristic facies 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• digitotalar dysmorphism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Freeman-Sheldon syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Sheldon-hall syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hypotonia, infantile, with psychomotor retardation and characteristic facies

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• temporal lobe epilepsy

  Inheritance: AD Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.66 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NALCN	NM_052867.4	c.800-23593A>G		intron_variant	Intron 7 of 43	ENST00000251127.11	NP_443099.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NALCN	ENST00000251127.11	c.800-23593A>G		intron_variant	Intron 7 of 43	1	NM_052867.4	ENSP00000251127.6

Frequencies

GnomAD3 genomes AF: 0.471 AC: 71478 AN: 151692 Hom.: 17175 Cov.: 30

Gnomad AFR AF: 0.384

Gnomad AMI AF: 0.582

Gnomad AMR AF: 0.518

Gnomad ASJ AF: 0.525

Gnomad EAS AF: 0.679

Gnomad SAS AF: 0.511

Gnomad FIN AF: 0.548

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.479

Gnomad OTH AF: 0.476

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

GnomAD4 genome AF: 0.471 AC: 71536 AN: 151810 Hom.: 17191 Cov.: 30 AF XY: 0.477 AC XY: 35417 AN XY: 74200

African (AFR) AF: 0.384 AC: 15903 AN: 41394

American (AMR) AF: 0.518 AC: 7905 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.525 AC: 1817 AN: 3464

East Asian (EAS) AF: 0.679 AC: 3478 AN: 5120

South Asian (SAS) AF: 0.509 AC: 2447 AN: 4804

European-Finnish (FIN) AF: 0.548 AC: 5778 AN: 10552

Middle Eastern (MID) AF: 0.439 AC: 129 AN: 294

European-Non Finnish (NFE) AF: 0.479 AC: 32531 AN: 67916

Other (OTH) AF: 0.482 AC: 1018 AN: 2110

Alfa AF: 0.471 Hom.: 27492

Bravo AF: 0.470

Asia WGS AF: 0.579 AC: 2012 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	2.0
DANN	Benign	0.41
PhyloP100		-0.089
Mutation Taster		=100/0	polymorphism (auto)

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: rs1538240; hg19: chr13-101968310;