rs76776920

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_052867.4(NALCN):c.2305C>T(p.His769Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0251 in 1,613,804 control chromosomes in the GnomAD database, including 602 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H769Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.018 ( 22 hom., cov: 33)

Exomes 𝑓: 0.026 ( 580 hom. )

Consequence

NALCN
NM_052867.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 9.36

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 -19 ACMG points.

PP2

Missense variant in the NALCN gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 63 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Gene score misZ: 4.9555 (above the threshold of 3.09). Trascript score misZ: 6.7536 (above the threshold of 3.09). GenCC associations: The gene is linked to congenital contractures of the limbs and face, hypotonia, and developmental delay, temporal lobe epilepsy, hypotonia, infantile, with psychomotor retardation and characteristic facies 1, Sheldon-hall syndrome, digitotalar dysmorphism, hypotonia, infantile, with psychomotor retardation and characteristic facies, Freeman-Sheldon syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.0089760125).

BP6

Variant 13-101110678-G-A is Benign according to our data. Variant chr13-101110678-G-A is described in ClinVar as Benign. ClinVar VariationId is 262255.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0185 (2812/152276) while in subpopulation NFE AF = 0.0296 (2010/68016). AF 95% confidence interval is 0.0285. There are 22 homozygotes in GnomAd4. There are 1291 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 22 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NALCN	NM_052867.4 link	c.2305C>T	p.His769Tyr	missense_variant	Exon 20 of 44	ENST00000251127.11	NP_443099.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NALCN	ENST00000251127.11 link	c.2305C>T	p.His769Tyr	missense_variant	Exon 20 of 44	1	NM_052867.4	ENSP00000251127.6

Frequencies

GnomAD3 genomes

AF:

0.0185

AC:

2813

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00485

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.0128

Gnomad ASJ

AF:

0.0415

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00683

Gnomad FIN

AF:

0.0171

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0295

Gnomad OTH

AF:

0.0205

GnomAD2 exomes

AF:

0.0199

AC:

5001

AN:

251062

AF XY:

0.0203

show subpopulations

Gnomad AFR exome

AF:

0.00468

Gnomad AMR exome

AF:

0.00674

Gnomad ASJ exome

AF:

0.0371

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0180

Gnomad NFE exome

AF:

0.0320

Gnomad OTH exome

AF:

0.0224

GnomAD4 exome

AF:

0.0258

AC:

37694

AN:

1461528

Hom.:

580

Cov.:

AF XY:

0.0255

AC XY:

18565

AN XY:

727090

show subpopulations

African (AFR)

AF:

0.00400

AC:

134

AN:

33476

American (AMR)

AF:

0.00809

AC:

362

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0408

AC:

1067

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39678

South Asian (SAS)

AF:

0.00621

AC:

536

AN:

86254

European-Finnish (FIN)

AF:

0.0208

AC:

1113

AN:

53406

Middle Eastern (MID)

AF:

0.0146

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0297

AC:

33022

AN:

1111714

Other (OTH)

AF:

0.0228

AC:

1376

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

1807

3614

5420

7227

9034

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1198

2396

3594

4792

5990

<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:

0.0185

AC:

2812

AN:

152276

Hom.:

Cov.:

AF XY:

0.0173

AC XY:

1291

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.00484

AC:

201

AN:

41550

American (AMR)

AF:

0.0128

AC:

196

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0415

AC:

144

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00684

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0171

AC:

181

AN:

10608

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0296

AC:

2010

AN:

68016

Other (OTH)

AF:

0.0203

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

146

292

437

583

729

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<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:

0.0267

Hom.:

201

Bravo

AF:

0.0179

TwinsUK

AF:

0.0243

AC:

ALSPAC

AF:

0.0340

AC:

131

ESP6500AA

AF:

0.00726

AC:

ESP6500EA

AF:

0.0303

AC:

261

ExAC

AF:

0.0209

AC:

2532

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.0269

EpiControl

AF:

0.0288

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 22, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Uncertain

-0.050

CADD

Uncertain

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.30

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.95

MetaRNN

Benign

0.0090

MetaSVM

Uncertain

0.40

MutationAssessor

Benign

0.90

PhyloP100

9.4

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-1.9

REVEL

Uncertain

0.48

Sift

Benign

0.91

Sift4G

Benign

1.0

Vest4

0.34

ClinPred

0.025

GERP RS

5.2

Varity_R

0.22

gMVP

0.60

Mutation Taster

=79/21

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