rs78817184

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_052867.4(NALCN):c.4977C>T(p.Asp1659Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0033 in 1,613,936 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0030 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0033 ( 22 hom. )

Consequence

NALCN
NM_052867.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.0910

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:

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

NALCN-AS1 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=-0.87).

BP6

Variant 13-101057985-G-A is Benign according to our data. Variant chr13-101057985-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 262264.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-101057985-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-0.091 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00302 (460/152290) while in subpopulation NFE AF= 0.00497 (338/68026). AF 95% confidence interval is 0.00453. There are 2 homozygotes in gnomad4. There are 193 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NALCN	NM_052867.4 link	c.4977C>T	p.Asp1659Asp	synonymous_variant	Exon 43 of 44	ENST00000251127.11	NP_443099.1	Q8IZF0-1A0A024RE05

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NALCN	ENST00000251127.11 link	c.4977C>T	p.Asp1659Asp	synonymous_variant	Exon 43 of 44	1	NM_052867.4	ENSP00000251127.6		Q8IZF0-1

Frequencies

GnomAD3 genomes

AF:

0.00302

AC:

459

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000628

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.00374

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00678

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00497

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00302

AC:

758

AN:

250996

Hom.:

AF XY:

0.00312

AC XY:

423

AN XY:

135694

show subpopulations

Gnomad AFR exome

AF:

0.000677

Gnomad AMR exome

AF:

0.000347

Gnomad ASJ exome

AF:

0.00497

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00732

Gnomad NFE exome

AF:

0.00445

Gnomad OTH exome

AF:

0.00310

GnomAD4 exome

AF:

0.00333

AC:

4869

AN:

1461646

Hom.:

Cov.:

AF XY:

0.00343

AC XY:

2492

AN XY:

727166

show subpopulations

Gnomad4 AFR exome

AF:

0.000926

Gnomad4 AMR exome

AF:

0.000425

Gnomad4 ASJ exome

AF:

0.00409

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000139

Gnomad4 FIN exome

AF:

0.00761

Gnomad4 NFE exome

AF:

0.00369

Gnomad4 OTH exome

AF:

0.00308

GnomAD4 genome

AF:

0.00302

AC:

460

AN:

152290

Hom.:

Cov.:

AF XY:

0.00259

AC XY:

193

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.000650

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.00374

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00678

Gnomad4 NFE

AF:

0.00497

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0226

Hom.:

1968

Bravo

AF:

0.00221

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00294

EpiControl

AF:

0.00320

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2025	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 08, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	NALCN: BP4, BP7, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

NALCN-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 11, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.051

DANN

Benign

0.75

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