rs41281140

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_052867.4(NALCN):c.2192+5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0119 in 1,611,668 control chromosomes in the GnomAD database, including 129 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0094 ( 2 hom., cov: 32)

Exomes 𝑓: 0.012 ( 127 hom. )

Consequence

NALCN
NM_052867.4 splice_region, intron

Scores

Splicing: ADA: 0.0001771

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.455

Publications

3 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=-0.73).

BP6

Variant 13-101124603-G-A is Benign according to our data. Variant chr13-101124603-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262253.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 = 0.00944 (1438/152260) while in subpopulation NFE AF = 0.0146 (996/68014). AF 95% confidence interval is 0.0139. There are 2 homozygotes in GnomAd4. There are 632 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NALCN	NM_052867.4 link	c.2192+5C>T		splice_region_variant, intron_variant	Intron 18 of 43	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.2192+5C>T		splice_region_variant, intron_variant	Intron 18 of 43	1	NM_052867.4	ENSP00000251127.6		Q8IZF0-1

Frequencies

GnomAD3 genomes

AF:

0.00945

AC:

1438

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00270

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0105

Gnomad ASJ

AF:

0.0199

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00594

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0146

Gnomad OTH

AF:

0.0139

GnomAD2 exomes

AF:

0.00870

AC:

2180

AN:

250566

AF XY:

0.00889

show subpopulations

Gnomad AFR exome

AF:

0.00228

Gnomad AMR exome

AF:

0.00518

Gnomad ASJ exome

AF:

0.0160

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00592

Gnomad NFE exome

AF:

0.0138

Gnomad OTH exome

AF:

0.0115

GnomAD4 exome

AF:

0.0122

AC:

17805

AN:

1459408

Hom.:

127

Cov.:

AF XY:

0.0118

AC XY:

8534

AN XY:

726072

show subpopulations

African (AFR)

AF:

0.00201

AC:

AN:

33398

American (AMR)

AF:

0.00622

AC:

277

AN:

44552

Ashkenazi Jewish (ASJ)

AF:

0.0157

AC:

410

AN:

26094

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39664

South Asian (SAS)

AF:

0.00122

AC:

105

AN:

85902

European-Finnish (FIN)

AF:

0.00540

AC:

288

AN:

53370

Middle Eastern (MID)

AF:

0.0141

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.0143

AC:

15880

AN:

1110332

Other (OTH)

AF:

0.0115

AC:

694

AN:

60338

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

745

1490

2234

2979

3724

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

572

1144

1716

2288

2860

<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:

0.00944

AC:

1438

AN:

152260

Hom.:

Cov.:

AF XY:

0.00849

AC XY:

632

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.00270

AC:

112

AN:

41546

American (AMR)

AF:

0.0105

AC:

160

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0199

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00166

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00594

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0146

AC:

996

AN:

68014

Other (OTH)

AF:

0.0137

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

146

218

291

364

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

100

<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:

0.0122

Hom.:

Bravo

AF:

0.00960

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.0132

EpiControl

AF:

0.0138

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NALCN: BP4, BS1, BS2 -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 06, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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

- -

Aug 06, 2021

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

- -

Hypotonia, infantile, with psychomotor retardation and characteristic facies 1;C4225398:Congenital contractures of the limbs and face, hypotonia, and developmental delay

Benign:1

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant has not been reported in the literature but is present in the Genome Aggregation Database (Highest reported MAF 1% (160/15278) including 2 homozygotes (https://gnomad.broadinstitute.org/variant/13-101124603-G-A?dataset=gnomad_r3). This variant is present in ClinVar, with several labs classifying this variant as Benign (Variation ID:262253). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant is an intronic variant with no predicted change in the amino acid sequence; computational prediction tools do not suggest that it alters splicing. However, further studies are needed to understand its impact. In summary, data on this variant suggests that this variant does not cause disease but requires further evidence. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

(source)

DANN

Benign

0.64

PhyloP100

-0.46

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00018

dbscSNV1_RF

Benign

0.0040

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

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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