rs661585

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.2118+9T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.466 in 1,613,500 control chromosomes in the GnomAD database, including 177,528 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.50 ( 19555 hom., cov: 32)

Exomes 𝑓: 0.46 ( 157973 hom. )

Consequence

NALCN
NM_052867.4 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.718

Publications

13 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: G2P, Labcorp Genetics (formerly Invitae)
hypotonia, infantile, with psychomotor retardation and characteristic facies 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
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

new If you want to explore the variant's impact on the transcript NM_052867.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

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=-0.86).

BP6

Variant 13-101143071-A-G is Benign according to our data. Variant chr13-101143071-A-G is described in ClinVar as Benign. ClinVar VariationId is 262252.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.6 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	Effect	Exon Rank	Protein	UniProt
NALCN	NM_052867.4	MANE Select	c.2118+9T>C	intron	N/A	NP_443099.1	Q8IZF0-1
NALCN	NM_001350748.2		c.2118+9T>C	intron	N/A	NP_001337677.1	A0A6Q8PFS9
NALCN	NM_001350749.2		c.2118+9T>C	intron	N/A	NP_001337678.1	Q8IZF0-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NALCN	ENST00000251127.11	TSL:1 MANE Select	c.2118+9T>C	intron	N/A	ENSP00000251127.6	Q8IZF0-1
NALCN	ENST00000675332.1		c.2118+9T>C	intron	N/A	ENSP00000501955.1	A0A6Q8PFS9
NALCN	ENST00000858715.1		c.2118+9T>C	intron	N/A	ENSP00000528774.1

Frequencies

GnomAD3 genomes

AF:

0.500

AC:

75923

AN:

151882

Hom.:

19526

Cov.:

show subpopulations

Gnomad AFR

AF:

0.606

Gnomad AMI

AF:

0.489

Gnomad AMR

AF:

0.401

Gnomad ASJ

AF:

0.468

Gnomad EAS

AF:

0.504

Gnomad SAS

AF:

0.547

Gnomad FIN

AF:

0.513

Gnomad MID

AF:

0.440

Gnomad NFE

AF:

0.455

Gnomad OTH

AF:

0.483

GnomAD2 exomes

AF:

0.484

AC:

121599

AN:

251416

AF XY:

0.481

show subpopulations

Gnomad AFR exome

AF:

0.614

Gnomad AMR exome

AF:

0.437

Gnomad ASJ exome

AF:

0.474

Gnomad EAS exome

AF:

0.503

Gnomad FIN exome

AF:

0.522

Gnomad NFE exome

AF:

0.456

Gnomad OTH exome

AF:

0.464

GnomAD4 exome

AF:

0.462

AC:

675835

AN:

1461500

Hom.:

157973

Cov.:

AF XY:

0.464

AC XY:

337467

AN XY:

727074

show subpopulations

African (AFR)

AF:

0.620

AC:

20744

AN:

33466

American (AMR)

AF:

0.437

AC:

19535

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.468

AC:

12231

AN:

26132

East Asian (EAS)

AF:

0.490

AC:

19452

AN:

39684

South Asian (SAS)

AF:

0.532

AC:

45915

AN:

86236

European-Finnish (FIN)

AF:

0.529

AC:

28245

AN:

53402

Middle Eastern (MID)

AF:

0.447

AC:

2578

AN:

5766

European-Non Finnish (NFE)

AF:

0.448

AC:

498351

AN:

1111712

Other (OTH)

AF:

0.477

AC:

28784

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

18203

36407

54610

72814

91017

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15122

30244

45366

60488

75610

<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:

0.500

AC:

76000

AN:

152000

Hom.:

19555

Cov.:

AF XY:

0.501

AC XY:

37242

AN XY:

74302

show subpopulations

African (AFR)

AF:

0.606

AC:

25114

AN:

41430

American (AMR)

AF:

0.401

AC:

6127

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.468

AC:

1623

AN:

3468

East Asian (EAS)

AF:

0.503

AC:

2598

AN:

5164

South Asian (SAS)

AF:

0.547

AC:

2636

AN:

4822

European-Finnish (FIN)

AF:

0.513

AC:

5416

AN:

10562

Middle Eastern (MID)

AF:

0.446

AC:

131

AN:

294

European-Non Finnish (NFE)

AF:

0.455

AC:

30895

AN:

67962

Other (OTH)

AF:

0.481

AC:

1016

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1908

3816

5725

7633

9541

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

688

1376

2064

2752

3440

<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:

0.469

Hom.:

54206

Bravo

AF:

0.498

Asia WGS

AF:

0.543

AC:

1884

AN:

3478

EpiCase

AF:

0.447

EpiControl

AF:

0.442

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

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

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

2.8

(source)

DANN

Benign

0.31

PhyloP100

-0.72

Mutation Taster

=100/0

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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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

Computational scores

Splicing

Publications

Other links and lift over