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.3714C>T(p.Thr1238Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.352 in 1,613,572 control chromosomes in the GnomAD database, including 103,286 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.30 ( 7708 hom., cov: 32)

Exomes 𝑓: 0.36 ( 95578 hom. )

Consequence

NALCN
NM_052867.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -2.37

Publications

22 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=-0.65).

BP6

Variant 13-101082860-G-A is Benign according to our data. Variant chr13-101082860-G-A is described in ClinVar as Benign. ClinVar VariationId is 262261.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.37 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.453 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_052867.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NALCN	NM_052867.4	MANE Select	c.3714C>T	p.Thr1238Thr	synonymous	Exon 33 of 44	NP_443099.1
NALCN	NM_001350748.2		c.3801C>T	p.Thr1267Thr	synonymous	Exon 34 of 45	NP_001337677.1
NALCN	NM_001350749.2		c.3714C>T	p.Thr1238Thr	synonymous	Exon 33 of 44	NP_001337678.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NALCN	ENST00000251127.11	TSL:1 MANE Select	c.3714C>T	p.Thr1238Thr	synonymous	Exon 33 of 44	ENSP00000251127.6
NALCN	ENST00000675332.1		c.3801C>T	p.Thr1267Thr	synonymous	Exon 34 of 45	ENSP00000501955.1
NALCN	ENST00000676315.1		c.3627C>T	p.Thr1209Thr	synonymous	Exon 32 of 43	ENSP00000501603.1

Frequencies

GnomAD3 genomes

AF:

0.298

AC:

45203

AN:

151912

Hom.:

7698

Cov.:

show subpopulations

Gnomad AFR

AF:

0.129

Gnomad AMI

AF:

0.396

Gnomad AMR

AF:

0.266

Gnomad ASJ

AF:

0.381

Gnomad EAS

AF:

0.468

Gnomad SAS

AF:

0.421

Gnomad FIN

AF:

0.450

Gnomad MID

AF:

0.342

Gnomad NFE

AF:

0.356

Gnomad OTH

AF:

0.318

GnomAD2 exomes

AF:

0.351

AC:

88076

AN:

251024

AF XY:

0.361

show subpopulations

Gnomad AFR exome

AF:

0.128

Gnomad AMR exome

AF:

0.239

Gnomad ASJ exome

AF:

0.373

Gnomad EAS exome

AF:

0.478

Gnomad FIN exome

AF:

0.430

Gnomad NFE exome

AF:

0.358

Gnomad OTH exome

AF:

0.357

GnomAD4 exome

AF:

0.357

AC:

522395

AN:

1461544

Hom.:

95578

Cov.:

AF XY:

0.361

AC XY:

262374

AN XY:

727106

show subpopulations

African (AFR)

AF:

0.125

AC:

4189

AN:

33470

American (AMR)

AF:

0.244

AC:

10909

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.382

AC:

9977

AN:

26132

East Asian (EAS)

AF:

0.428

AC:

16998

AN:

39696

South Asian (SAS)

AF:

0.429

AC:

36972

AN:

86240

European-Finnish (FIN)

AF:

0.425

AC:

22702

AN:

53412

Middle Eastern (MID)

AF:

0.368

AC:

2120

AN:

5766

European-Non Finnish (NFE)

AF:

0.357

AC:

397051

AN:

1111724

Other (OTH)

AF:

0.356

AC:

21477

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

17676

35352

53027

70703

88379

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12650

25300

37950

50600

63250

<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:

0.297

AC:

45228

AN:

152028

Hom.:

7708

Cov.:

AF XY:

0.308

AC XY:

22855

AN XY:

74290

show subpopulations

African (AFR)

AF:

0.129

AC:

5358

AN:

41472

American (AMR)

AF:

0.266

AC:

4060

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.381

AC:

1320

AN:

3468

East Asian (EAS)

AF:

0.468

AC:

2415

AN:

5156

South Asian (SAS)

AF:

0.422

AC:

2030

AN:

4814

European-Finnish (FIN)

AF:

0.450

AC:

4747

AN:

10546

Middle Eastern (MID)

AF:

0.327

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.355

AC:

24164

AN:

67974

Other (OTH)

AF:

0.320

AC:

677

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1529

3058

4588

6117

7646

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

474

948

1422

1896

2370

<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:

0.335

Hom.:

35292

Bravo

AF:

0.277

Asia WGS

AF:

0.400

AC:

1393

AN:

3478

EpiCase

AF:

0.359

EpiControl

AF:

0.364

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Congenital contractures of the limbs and face, hypotonia, and developmental delay (1)

Hypotonia, infantile, with psychomotor retardation and characteristic facies 1 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.65

CADD

Benign

0.77

(source)

DANN

Benign

0.78

PhyloP100

-2.4

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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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NM_052867.4:c.3714C>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over