rs9518331

Positions:

• chr13-101173903-G-T

Variant summary

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

The ENST00000251127.11(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 ENST00000251127.11 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.29

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=-0.92).
• 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/exons	MANE	Protein	UniProt
NALCN	NM_052867.4	c.1839+2397C>A		intron_variant		ENST00000251127.11	NP_443099.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NALCN	ENST00000251127.11	c.1839+2397C>A		intron_variant		1	NM_052867.4	ENSP00000251127	P1

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

Gnomad4 AFR AF: 0.144

Gnomad4 AMR AF: 0.187

Gnomad4 ASJ AF: 0.262

Gnomad4 EAS AF: 0.0251

Gnomad4 SAS AF: 0.286

Gnomad4 FIN AF: 0.309

Gnomad4 NFE AF: 0.327

Gnomad4 OTH AF: 0.247

Alfa AF: 0.286 Hom.: 801

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

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: rs9518331; hg19: chr13-101826254;