rs17582557

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_052867.4(NALCN):c.1836A>G(p.Lys612Lys) variant causes a synonymous change. The variant allele was found at a frequency of 0.0475 in 1,581,280 control chromosomes in the GnomAD database, including 2,031 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.037 ( 151 hom., cov: 33)

Exomes 𝑓: 0.049 ( 1880 hom. )

Consequence

NALCN
NM_052867.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 5.10

Publications

6 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.5).

BP6

Variant 13-101176303-T-C is Benign according to our data. Variant chr13-101176303-T-C is described in ClinVar as Benign. ClinVar VariationId is 262251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0515 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.1836A>G	p.Lys612Lys	synonymous	Exon 15 of 44	NP_443099.1
NALCN	NM_001350748.2		c.1836A>G	p.Lys612Lys	synonymous	Exon 15 of 45	NP_001337677.1
NALCN	NM_001350749.2		c.1836A>G	p.Lys612Lys	synonymous	Exon 15 of 44	NP_001337678.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NALCN	ENST00000251127.11	TSL:1 MANE Select	c.1836A>G	p.Lys612Lys	synonymous	Exon 15 of 44	ENSP00000251127.6
NALCN	ENST00000675332.1		c.1836A>G	p.Lys612Lys	synonymous	Exon 15 of 45	ENSP00000501955.1
NALCN	ENST00000676315.1		c.1749A>G	p.Lys583Lys	synonymous	Exon 14 of 43	ENSP00000501603.1

Frequencies

GnomAD3 genomes

AF:

0.0374

AC:

5684

AN:

152162

Hom.:

151

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00970

Gnomad AMI

AF:

0.180

Gnomad AMR

AF:

0.0300

Gnomad ASJ

AF:

0.0620

Gnomad EAS

AF:

0.000962

Gnomad SAS

AF:

0.0151

Gnomad FIN

AF:

0.0639

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.0530

Gnomad OTH

AF:

0.0330

GnomAD2 exomes

AF:

0.0429

AC:

9582

AN:

223590

AF XY:

0.0437

show subpopulations

Gnomad AFR exome

AF:

0.00776

Gnomad AMR exome

AF:

0.0374

Gnomad ASJ exome

AF:

0.0613

Gnomad EAS exome

AF:

0.000315

Gnomad FIN exome

AF:

0.0668

Gnomad NFE exome

AF:

0.0549

Gnomad OTH exome

AF:

0.0577

GnomAD4 exome

AF:

0.0486

AC:

69416

AN:

1428998

Hom.:

1880

Cov.:

AF XY:

0.0483

AC XY:

34312

AN XY:

710378

show subpopulations

African (AFR)

AF:

0.00690

AC:

217

AN:

31446

American (AMR)

AF:

0.0353

AC:

1342

AN:

38060

Ashkenazi Jewish (ASJ)

AF:

0.0588

AC:

1484

AN:

25240

East Asian (EAS)

AF:

0.000186

AC:

AN:

37706

South Asian (SAS)

AF:

0.0169

AC:

1349

AN:

79856

European-Finnish (FIN)

AF:

0.0624

AC:

3279

AN:

52546

Middle Eastern (MID)

AF:

0.0434

AC:

245

AN:

5644

European-Non Finnish (NFE)

AF:

0.0535

AC:

58866

AN:

1099624

Other (OTH)

AF:

0.0446

AC:

2627

AN:

58876

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

2749

5498

8247

10996

13745

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2136

4272

6408

8544

10680

<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:

0.0373

AC:

5682

AN:

152282

Hom.:

151

Cov.:

AF XY:

0.0369

AC XY:

2750

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.00967

AC:

402

AN:

41570

American (AMR)

AF:

0.0299

AC:

458

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0620

AC:

215

AN:

3470

East Asian (EAS)

AF:

0.000965

AC:

AN:

5184

South Asian (SAS)

AF:

0.0151

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0639

AC:

677

AN:

10596

Middle Eastern (MID)

AF:

0.0578

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0530

AC:

3602

AN:

68016

Other (OTH)

AF:

0.0326

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

267

533

800

1066

1333

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

140

210

280

350

<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:

0.0493

Hom.:

102

Bravo

AF:

0.0343

Asia WGS

AF:

0.0120

AC:

AN:

3474

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.72

PhyloP100

5.1

PromoterAI

-0.011

Neutral

(source)

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

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