rs9518320

Variant names:

• chr13-101167478-A-G
• rs9518320
• NM_052867.4:c.1839+8822T>C

Variant summary

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

The NM_052867.4(NALCN):​c.1839+8822T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.242 in 152,132 control chromosomes in the GnomAD database, including 5,223 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 0.24 (5223 hom., cov: 32)
• Consequence: NALCN NM_052867.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.904
• Publications: 3 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=-1.0).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.318 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NALCN	NM_052867.4	c.1839+8822T>C		intron_variant	Intron 15 of 43	ENST00000251127.11	NP_443099.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NALCN	ENST00000251127.11	c.1839+8822T>C		intron_variant	Intron 15 of 43	1	NM_052867.4	ENSP00000251127.6

Frequencies

GnomAD3 genomes AF: 0.242 AC: 36771 AN: 152014 Hom.: 5225 Cov.: 32

Gnomad AFR AF: 0.126

Gnomad AMI AF: 0.409

Gnomad AMR AF: 0.192

Gnomad ASJ AF: 0.262

Gnomad EAS AF: 0.0334

Gnomad SAS AF: 0.282

Gnomad FIN AF: 0.313

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.322

Gnomad OTH AF: 0.252

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

GnomAD4 genome AF: 0.242 AC: 36769 AN: 152132 Hom.: 5223 Cov.: 32 AF XY: 0.240 AC XY: 17855 AN XY: 74374

African (AFR) AF: 0.126 AC: 5250 AN: 41540

American (AMR) AF: 0.192 AC: 2936 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.262 AC: 909 AN: 3472

East Asian (EAS) AF: 0.0336 AC: 174 AN: 5172

South Asian (SAS) AF: 0.281 AC: 1353 AN: 4814

European-Finnish (FIN) AF: 0.313 AC: 3311 AN: 10566

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.322 AC: 21879 AN: 67964

Other (OTH) AF: 0.250 AC: 526 AN: 2106

Alfa AF: 0.275 Hom.: 783

Bravo AF: 0.227

Asia WGS AF: 0.165 AC: 572 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	3.4
DANN	Benign	0.70
PhyloP100		-0.90
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: rs9518320; hg19: chr13-101819829;