rs9513877

Variant names:

• chr13-101273988-G-A
• rs9513877
• NM_052867.4:c.1134+9945C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_052867.4(NALCN):​c.1134+9945C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.307 in 151,566 control chromosomes in the GnomAD database, including 7,560 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 0.31 (7560 hom., cov: 31)
• Consequence: NALCN NM_052867.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.41
• 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=-0.97).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.358 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_052867.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NALCN	NM_052867.4	MANE Select	c.1134+9945C>T		intron	N/A	NP_443099.1	Q8IZF0-1
	NALCN	NM_001350748.2		c.1134+9945C>T		intron	N/A	NP_001337677.1	A0A6Q8PFS9
	NALCN	NM_001350749.2		c.1134+9945C>T		intron	N/A	NP_001337678.1	Q8IZF0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NALCN	ENST00000251127.11	TSL:1 MANE Select	c.1134+9945C>T		intron	N/A	ENSP00000251127.6	Q8IZF0-1
	NALCN	ENST00000470333.1	TSL:1	n.1230+9945C>T		intron	N/A
	NALCN	ENST00000675332.1		c.1134+9945C>T		intron	N/A	ENSP00000501955.1	A0A6Q8PFS9

Frequencies

GnomAD3 genomes AF: 0.308 AC: 46589 AN: 151460 Hom.: 7560 Cov.: 31

Gnomad AFR AF: 0.233

Gnomad AMI AF: 0.390

Gnomad AMR AF: 0.268

Gnomad ASJ AF: 0.257

Gnomad EAS AF: 0.196

Gnomad SAS AF: 0.320

Gnomad FIN AF: 0.368

Gnomad MID AF: 0.226

Gnomad NFE AF: 0.362

Gnomad OTH AF: 0.294

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

GnomAD4 genome AF: 0.307 AC: 46594 AN: 151566 Hom.: 7560 Cov.: 31 AF XY: 0.308 AC XY: 22797 AN XY: 74046

African (AFR) AF: 0.233 AC: 9605 AN: 41250

American (AMR) AF: 0.268 AC: 4071 AN: 15216

Ashkenazi Jewish (ASJ) AF: 0.257 AC: 894 AN: 3472

East Asian (EAS) AF: 0.196 AC: 1011 AN: 5164

South Asian (SAS) AF: 0.320 AC: 1539 AN: 4812

European-Finnish (FIN) AF: 0.368 AC: 3844 AN: 10438

Middle Eastern (MID) AF: 0.228 AC: 66 AN: 290

European-Non Finnish (NFE) AF: 0.362 AC: 24597 AN: 67906

Other (OTH) AF: 0.290 AC: 611 AN: 2106

Alfa AF: 0.338 Hom.: 14952

Bravo AF: 0.295

Asia WGS AF: 0.221 AC: 773 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.034
DANN	Benign	0.44
PhyloP100		-1.4
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: rs9513877; hg19: chr13-101926339;