rs3916906

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_052867.4(NALCN):c.1593C>T(p.Val531Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.335 in 1,602,124 control chromosomes in the GnomAD database, including 95,758 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V531V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.27 ( 6585 hom., cov: 33)

Exomes 𝑓: 0.34 ( 89173 hom. )

Consequence

NALCN
NM_052867.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -1.54

Publications

16 publications found

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 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

NALCN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BP6

Variant 13-101229426-G-A is Benign according to our data. Variant chr13-101229426-G-A is described in ClinVar as Benign. ClinVar VariationId is 262250.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.54 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.362 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NALCN	NM_052867.4 link	c.1593C>T	p.Val531Val	synonymous_variant	Exon 13 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.1593C>T	p.Val531Val	synonymous_variant	Exon 13 of 44	1	NM_052867.4	ENSP00000251127.6		Q8IZF0-1

Frequencies

GnomAD3 genomes

AF:

0.271

AC:

41121

AN:

151930

Hom.:

6584

Cov.:

show subpopulations

Gnomad AFR

AF:

0.137

Gnomad AMI

AF:

0.436

Gnomad AMR

AF:

0.202

Gnomad ASJ

AF:

0.289

Gnomad EAS

AF:

0.0355

Gnomad SAS

AF:

0.297

Gnomad FIN

AF:

0.367

Gnomad MID

AF:

0.241

Gnomad NFE

AF:

0.366

Gnomad OTH

AF:

0.263

GnomAD2 exomes

AF:

0.283

AC:

68633

AN:

242156

AF XY:

0.293

show subpopulations

Gnomad AFR exome

AF:

0.135

Gnomad AMR exome

AF:

0.146

Gnomad ASJ exome

AF:

0.297

Gnomad EAS exome

AF:

0.0370

Gnomad FIN exome

AF:

0.365

Gnomad NFE exome

AF:

0.359

Gnomad OTH exome

AF:

0.299

GnomAD4 exome

AF:

0.341

AC:

494986

AN:

1450078

Hom.:

89173

Cov.:

AF XY:

0.342

AC XY:

246460

AN XY:

721260

show subpopulations

African (AFR)

AF:

0.132

AC:

4370

AN:

32994

American (AMR)

AF:

0.155

AC:

6610

AN:

42574

Ashkenazi Jewish (ASJ)

AF:

0.296

AC:

7677

AN:

25924

East Asian (EAS)

AF:

0.0336

AC:

1303

AN:

38830

South Asian (SAS)

AF:

0.308

AC:

25901

AN:

84172

European-Finnish (FIN)

AF:

0.365

AC:

19391

AN:

53094

Middle Eastern (MID)

AF:

0.213

AC:

1224

AN:

5738

European-Non Finnish (NFE)

AF:

0.370

AC:

409858

AN:

1106890

Other (OTH)

AF:

0.312

AC:

18652

AN:

59862

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

15464

30928

46391

61855

77319

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12680

25360

38040

50720

63400

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.270

AC:

41118

AN:

152046

Hom.:

6585

Cov.:

AF XY:

0.269

AC XY:

19973

AN XY:

74312

show subpopulations

African (AFR)

AF:

0.137

AC:

5687

AN:

41498

American (AMR)

AF:

0.202

AC:

3080

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.289

AC:

1003

AN:

3468

East Asian (EAS)

AF:

0.0358

AC:

185

AN:

5172

South Asian (SAS)

AF:

0.296

AC:

1430

AN:

4826

European-Finnish (FIN)

AF:

0.367

AC:

3867

AN:

10542

Middle Eastern (MID)

AF:

0.243

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.366

AC:

24851

AN:

67960

Other (OTH)

AF:

0.260

AC:

548

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

1488

2975

4463

5950

7438

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

436

872

1308

1744

2180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.302

Hom.:

4554

Bravo

AF:

0.252

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jul 15, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hypotonia, infantile, with psychomotor retardation and characteristic facies 1

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Congenital contractures of the limbs and face, hypotonia, and developmental delay

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

0.082

(source)

DANN

Benign

0.76

PhyloP100

-1.5

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over