13-101173903-G-T

Variant names:

• chr13-101173903-G-T
• rs9518331
• NM_052867.4:c.1839+2397C>A

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+2397C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.248 in 152,000 control chromosomes in the GnomAD database, including 5,397 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 0.25 (5397 hom., cov: 32)
• Consequence: NALCN NM_052867.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.29
• 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=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.323 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NALCN	NM_052867.4	c.1839+2397C>A		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+2397C>A		intron_variant	Intron 15 of 43	1	NM_052867.4	ENSP00000251127.6

Frequencies

GnomAD3 genomes AF: 0.248 AC: 37683 AN: 151880 Hom.: 5398 Cov.: 32

Gnomad AFR AF: 0.144

Gnomad AMI AF: 0.426

Gnomad AMR AF: 0.187

Gnomad ASJ AF: 0.262

Gnomad EAS AF: 0.0249

Gnomad SAS AF: 0.287

Gnomad FIN AF: 0.309

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.327

Gnomad OTH AF: 0.250

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

GnomAD4 genome AF: 0.248 AC: 37685 AN: 152000 Hom.: 5397 Cov.: 32 AF XY: 0.246 AC XY: 18240 AN XY: 74286

African (AFR) AF: 0.144 AC: 5985 AN: 41476

American (AMR) AF: 0.187 AC: 2857 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.262 AC: 908 AN: 3472

East Asian (EAS) AF: 0.0251 AC: 130 AN: 5180

South Asian (SAS) AF: 0.286 AC: 1375 AN: 4816

European-Finnish (FIN) AF: 0.309 AC: 3245 AN: 10518

Middle Eastern (MID) AF: 0.197 AC: 58 AN: 294

European-Non Finnish (NFE) AF: 0.327 AC: 22217 AN: 67952

Other (OTH) AF: 0.247 AC: 522 AN: 2110

Alfa AF: 0.280 Hom.: 806

Bravo AF: 0.234

Asia WGS AF: 0.162 AC: 564 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.060
DANN	Benign	0.22
PhyloP100		-4.3
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: rs9518331; hg19: chr13-101826254;