13-101113823-C-T

Variant names:

• chr13-101113823-C-T
• rs17484734
• NM_052867.4:c.2193-2597G>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.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
• Publications: 5 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=-0.96).
• 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 rank	MANE	Protein	UniProt
NALCN	NM_052867.4	c.2193-2597G>A		intron_variant	Intron 18 of 43	ENST00000251127.11	NP_443099.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NALCN	ENST00000251127.11	c.2193-2597G>A		intron_variant	Intron 18 of 43	1	NM_052867.4	ENSP00000251127.6

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

African (AFR) AF: 0.0154 AC: 640 AN: 41540

American (AMR) AF: 0.0560 AC: 857 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0945 AC: 328 AN: 3472

East Asian (EAS) AF: 0.000773 AC: 4 AN: 5172

South Asian (SAS) AF: 0.0234 AC: 113 AN: 4828

European-Finnish (FIN) AF: 0.0566 AC: 600 AN: 10606

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0720 AC: 4898 AN: 68010

Other (OTH) AF: 0.0565 AC: 119 AN: 2108

Alfa AF: 0.0648 Hom.: 709

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
PhyloP100		-0.55
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: rs17484734; hg19: chr13-101766174;