13-101398739-A-G

Variant names:

• chr13-101398739-A-G
• rs9557635
• NM_052867.4:c.108+280T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_052867.4(NALCN):​c.108+280T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.695 in 151,916 control chromosomes in the GnomAD database, including 38,344 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.69 (38344 hom., cov: 30)
• Consequence: NALCN NM_052867.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.04
• Publications: 13 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 13-101398739-A-G is Benign according to our data. Variant chr13-101398739-A-G is described in ClinVar as Benign. ClinVar VariationId is 1265292.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.899 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NALCN	NM_052867.4	MANE Select	c.108+280T>C		intron	N/A	NP_443099.1
	NALCN	NM_001350748.2		c.108+280T>C		intron	N/A	NP_001337677.1
	NALCN	NM_001350749.2		c.108+280T>C		intron	N/A	NP_001337678.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NALCN	ENST00000251127.11	TSL:1 MANE Select	c.108+280T>C		intron	N/A	ENSP00000251127.6
	NALCN	ENST00000376200.6	TSL:1	c.108+280T>C		intron	N/A	ENSP00000365373.5
	NALCN	ENST00000470333.1	TSL:1	n.204+280T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.695 AC: 105428 AN: 151798 Hom.: 38271 Cov.: 30

Gnomad AFR AF: 0.906

Gnomad AMI AF: 0.784

Gnomad AMR AF: 0.708

Gnomad ASJ AF: 0.573

Gnomad EAS AF: 0.854

Gnomad SAS AF: 0.676

Gnomad FIN AF: 0.629

Gnomad MID AF: 0.592

Gnomad NFE AF: 0.568

Gnomad OTH AF: 0.670

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

GnomAD4 genome AF: 0.695 AC: 105562 AN: 151916 Hom.: 38344 Cov.: 30 AF XY: 0.698 AC XY: 51779 AN XY: 74210

African (AFR) AF: 0.907 AC: 37608 AN: 41486

American (AMR) AF: 0.708 AC: 10809 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.573 AC: 1990 AN: 3470

East Asian (EAS) AF: 0.855 AC: 4389 AN: 5136

South Asian (SAS) AF: 0.677 AC: 3250 AN: 4804

European-Finnish (FIN) AF: 0.629 AC: 6619 AN: 10518

Middle Eastern (MID) AF: 0.575 AC: 169 AN: 294

European-Non Finnish (NFE) AF: 0.568 AC: 38593 AN: 67930

Other (OTH) AF: 0.674 AC: 1422 AN: 2110

Alfa AF: 0.635 Hom.: 64312

Bravo AF: 0.712

Asia WGS AF: 0.766 AC: 2665 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jul 03, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	8.5
DANN	Benign	0.74
PhyloP100		1.0
PromoterAI		0.0078	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs9557635; hg19: chr13-102051090;