rs9513851

Variant names:

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.3210C>T(p.Asn1070Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0645 in 1,611,716 control chromosomes in the GnomAD database, including 3,776 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.063 ( 332 hom., cov: 32)

Exomes 𝑓: 0.065 ( 3444 hom. )

Consequence

NALCN
NM_052867.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.39

Publications

11 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=-0.48).

BP6

Variant 13-101095633-G-A is Benign according to our data. Variant chr13-101095633-G-A is described in ClinVar as Benign. ClinVar VariationId is 262259.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.38 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.104 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NALCN	NM_052867.4 link	c.3210C>T	p.Asn1070Asn	synonymous_variant	Exon 28 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.3210C>T	p.Asn1070Asn	synonymous_variant	Exon 28 of 44	1	NM_052867.4	ENSP00000251127.6		Q8IZF0-1

Frequencies

GnomAD3 genomes

AF:

0.0633

AC:

9608

AN:

151756

Hom.:

330

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0742

Gnomad AMI

AF:

0.0407

Gnomad AMR

AF:

0.0489

Gnomad ASJ

AF:

0.100

Gnomad EAS

AF:

0.0340

Gnomad SAS

AF:

0.112

Gnomad FIN

AF:

0.0384

Gnomad MID

AF:

0.0981

Gnomad NFE

AF:

0.0612

Gnomad OTH

AF:

0.0535

GnomAD2 exomes

AF:

0.0627

AC:

15678

AN:

249948

AF XY:

0.0670

show subpopulations

Gnomad AFR exome

AF:

0.0706

Gnomad AMR exome

AF:

0.0304

Gnomad ASJ exome

AF:

0.0963

Gnomad EAS exome

AF:

0.0375

Gnomad FIN exome

AF:

0.0445

Gnomad NFE exome

AF:

0.0624

Gnomad OTH exome

AF:

0.0653

GnomAD4 exome

AF:

0.0647

AC:

94412

AN:

1459842

Hom.:

3444

Cov.:

AF XY:

0.0666

AC XY:

48389

AN XY:

726226

show subpopulations

African (AFR)

AF:

0.0713

AC:

2382

AN:

33386

American (AMR)

AF:

0.0317

AC:

1413

AN:

44624

Ashkenazi Jewish (ASJ)

AF:

0.0945

AC:

2465

AN:

26088

East Asian (EAS)

AF:

0.0334

AC:

1324

AN:

39634

South Asian (SAS)

AF:

0.114

AC:

9760

AN:

85954

European-Finnish (FIN)

AF:

0.0473

AC:

2525

AN:

53348

Middle Eastern (MID)

AF:

0.0989

AC:

569

AN:

5756

European-Non Finnish (NFE)

AF:

0.0628

AC:

69799

AN:

1110756

Other (OTH)

AF:

0.0692

AC:

4175

AN:

60296

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.437

Heterozygous variant carriers

4415

8830

13244

17659

22074

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2684

5368

8052

10736

13420

<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:

0.0633

AC:

9621

AN:

151874

Hom.:

332

Cov.:

AF XY:

0.0636

AC XY:

4719

AN XY:

74242

show subpopulations

African (AFR)

AF:

0.0742

AC:

3074

AN:

41404

American (AMR)

AF:

0.0489

AC:

744

AN:

15230

Ashkenazi Jewish (ASJ)

AF:

0.100

AC:

347

AN:

3468

East Asian (EAS)

AF:

0.0345

AC:

178

AN:

5164

South Asian (SAS)

AF:

0.112

AC:

538

AN:

4812

European-Finnish (FIN)

AF:

0.0384

AC:

405

AN:

10546

Middle Eastern (MID)

AF:

0.102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0612

AC:

4157

AN:

67948

Other (OTH)

AF:

0.0529

AC:

111

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

459

917

1376

1834

2293

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

118

236

354

472

590

<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:

0.0651

Hom.:

367

Bravo

AF:

0.0626

Asia WGS

AF:

0.0660

AC:

229

AN:

3478

EpiCase

AF:

0.0631

EpiControl

AF:

0.0644

ClinVar

Significance: Benign

Submissions summary: Benign:4

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 03, 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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.48

CADD

Benign

4.7

(source)

DANN

Benign

0.68

PhyloP100

1.4

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

Publications

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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