13-101057246-C-G

Position:

• chr13-101057246-C-G

Variant summary

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

The ENST00000251127.11(NALCN):​c.5023+693G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.428 in 152,226 control chromosomes in the GnomAD database, including 14,441 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 0.43 (14431 hom., cov: 32)
  • Exomes 𝑓: 0.29 (10 hom.)
• Consequence: NALCN ENST00000251127.11 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.26

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-AS1 (HGNC:42743): (NALCN antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.572 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NALCN	NM_052867.4	c.5023+693G>C		intron_variant		ENST00000251127.11	NP_443099.1
NALCN-AS1	NR_047687.1	n.1067C>G		non_coding_transcript_exon_variant	7/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NALCN	ENST00000251127.11	c.5023+693G>C		intron_variant		1	NM_052867.4	ENSP00000251127	P1
NALCN-AS1	ENST00000457843.1	n.1067C>G		non_coding_transcript_exon_variant	7/8	2

Frequencies

GnomAD3 genomes AF: 0.428 AC: 65081 AN: 151914 Hom.: 14409 Cov.: 32

Gnomad AFR AF: 0.497

Gnomad AMI AF: 0.418

Gnomad AMR AF: 0.324

Gnomad ASJ AF: 0.437

Gnomad EAS AF: 0.588

Gnomad SAS AF: 0.512

Gnomad FIN AF: 0.546

Gnomad MID AF: 0.405

Gnomad NFE AF: 0.373

Gnomad OTH AF: 0.432

GnomAD4 exome AF: 0.289 AC: 56 AN: 194 Hom.: 10 Cov.: 0 AF XY: 0.304 AC XY: 28 AN XY: 92

Gnomad4 AFR exome AF: 1.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 EAS exome AF: 0.500

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.299

Gnomad4 OTH exome AF: 0.500

GnomAD4 genome AF: 0.429 AC: 65150 AN: 152032 Hom.: 14431 Cov.: 32 AF XY: 0.438 AC XY: 32581 AN XY: 74314

Gnomad4 AFR AF: 0.498

Gnomad4 AMR AF: 0.324

Gnomad4 ASJ AF: 0.437

Gnomad4 EAS AF: 0.589

Gnomad4 SAS AF: 0.513

Gnomad4 FIN AF: 0.546

Gnomad4 NFE AF: 0.373

Gnomad4 OTH AF: 0.435

Alfa AF: 0.255 Hom.: 608

Bravo AF: 0.413

Asia WGS AF: 0.523 AC: 1823 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.082
DANN	Benign	0.52

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: rs638732; hg19: chr13-101709598;