rs34513106

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_052867.4(NALCN):c.2520C>T(p.Val840=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00888 in 1,614,104 control chromosomes in the GnomAD database, including 124 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 20 hom., cov: 33)

Exomes 𝑓: 0.0084 ( 104 hom. )

Consequence

NALCN
NM_052867.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.372

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.52).

BP6

Variant 13-101107546-G-A is Benign according to our data. Variant chr13-101107546-G-A is described in ClinVar as [Benign]. Clinvar id is 262257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.372 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0132 (2015/152300) while in subpopulation AFR AF= 0.0272 (1130/41562). AF 95% confidence interval is 0.0259. There are 20 homozygotes in gnomad4. There are 951 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 21 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NALCN	NM_052867.4 linkuse as main transcript	c.2520C>T	p.Val840=	synonymous_variant	22/44	ENST00000251127.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NALCN	ENST00000251127.11 linkuse as main transcript	c.2520C>T	p.Val840=	synonymous_variant	22/44	1	NM_052867.4	P1	Q8IZF0-1

Frequencies

GnomAD3 genomes

AF:

0.0132

AC:

2015

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0272

Gnomad AMI

AF:

0.0219

Gnomad AMR

AF:

0.0100

Gnomad ASJ

AF:

0.0181

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00932

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.00836

Gnomad OTH

AF:

0.00908

GnomAD3 exomes

AF:

0.00879

AC:

2208

AN:

251220

Hom.:

AF XY:

0.00880

AC XY:

1194

AN XY:

135754

show subpopulations

Gnomad AFR exome

AF:

0.0287

Gnomad AMR exome

AF:

0.00550

Gnomad ASJ exome

AF:

0.0216

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0105

Gnomad FIN exome

AF:

0.000370

Gnomad NFE exome

AF:

0.00841

Gnomad OTH exome

AF:

0.00816

GnomAD4 exome

AF:

0.00842

AC:

12314

AN:

1461804

Hom.:

104

Cov.:

AF XY:

0.00867

AC XY:

6302

AN XY:

727202

show subpopulations

Gnomad4 AFR exome

AF:

0.0271

Gnomad4 AMR exome

AF:

0.00597

Gnomad4 ASJ exome

AF:

0.0214

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00998

Gnomad4 FIN exome

AF:

0.000693

Gnomad4 NFE exome

AF:

0.00807

Gnomad4 OTH exome

AF:

0.00980

GnomAD4 genome

AF:

0.0132

AC:

2015

AN:

152300

Hom.:

Cov.:

AF XY:

0.0128

AC XY:

951

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.0272

Gnomad4 AMR

AF:

0.0100

Gnomad4 ASJ

AF:

0.0181

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00933

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00838

Gnomad4 OTH

AF:

0.00899

Alfa

AF:

0.0117

Hom.:

Bravo

AF:

0.0144

Asia WGS

AF:

0.00808

AC:

AN:

3478

EpiCase

AF:

0.0105

EpiControl

AF:

0.00990

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 06, 2018	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

Cadd

Benign

0.18

Dann

Benign

0.69

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over