13-101113823-C-T

Variant summary

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

The NM_052867.4(NALCN):c.2193-2597G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0503 in 152,236 control chromosomes in the GnomAD database, including 251 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 0.050 (251 hom., cov: 33)
• Consequence: NALCN NM_052867.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.553

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=-0.96).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0703 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NALCN	NM_052867.4	c.2193-2597G>A		intron_variant		ENST00000251127.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NALCN	ENST00000251127.11	c.2193-2597G>A		intron_variant		1	NM_052867.4	P1

Frequencies

GnomAD3 genomes AF: 0.0503 AC: 7654 AN: 152118 Hom.: 251 Cov.: 33

Gnomad AFR AF: 0.0155

Gnomad AMI AF: 0.0888

Gnomad AMR AF: 0.0561

Gnomad ASJ AF: 0.0945

Gnomad EAS AF: 0.000772

Gnomad SAS AF: 0.0236

Gnomad FIN AF: 0.0566

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0720

Gnomad OTH AF: 0.0570

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

GnomAD4 genome AF: 0.0503 AC: 7650 AN: 152236 Hom.: 251 Cov.: 33 AF XY: 0.0487 AC XY: 3627 AN XY: 74448

Gnomad4 AFR AF: 0.0154

Gnomad4 AMR AF: 0.0560

Gnomad4 ASJ AF: 0.0945

Gnomad4 EAS AF: 0.000773

Gnomad4 SAS AF: 0.0234

Gnomad4 FIN AF: 0.0566

Gnomad4 NFE AF: 0.0720

Gnomad4 OTH AF: 0.0565

Alfa AF: 0.0666 Hom.: 502

Bravo AF: 0.0483

Asia WGS AF: 0.0120 AC: 40 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
Cadd	Benign	0.47
Dann	Benign	0.43

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: rs17484734; hg19: chr13-101766174;