Genetic Variant NALCN:c.5023+693G>C (chr13-101057246-C-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_052867.4(NALCN):c.5023+693G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.428 in 152,226 control chromosomes in the GnomAD database, including 14,441 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.43 ( 14431 hom., cov: 32)

Exomes 𝑓: 0.29 ( 10 hom. )

Consequence

NALCN
NM_052867.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.26

Publications

2 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 links:

NALCN-AS1 (HGNC:42743): (NALCN antisense RNA 1)

NALCN-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.572 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.5023+693G>C	intron	N/A	NP_443099.1	Q8IZF0-1
NALCN	NM_001350748.2		c.5110+693G>C	intron	N/A	NP_001337677.1	A0A6Q8PFS9
NALCN	NM_001350749.2		c.5023+693G>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.5023+693G>C	intron	N/A	ENSP00000251127.6	Q8IZF0-1
NALCN	ENST00000675332.1		c.5110+693G>C	intron	N/A	ENSP00000501955.1	A0A6Q8PFS9
NALCN	ENST00000858715.1		c.5023+693G>C	intron	N/A	ENSP00000528774.1

Frequencies

GnomAD3 genomes

AF:

0.428

AC:

65081

AN:

151914

Hom.:

14409

Cov.:

show subpopulations

Gnomad AFR

AF:

0.497

Gnomad AMI

AF:

0.418

Gnomad AMR

AF:

0.324

Gnomad ASJ

AF:

0.437

Gnomad EAS

AF:

0.588

Gnomad SAS

AF:

0.512

Gnomad FIN

AF:

0.546

Gnomad MID

AF:

0.405

Gnomad NFE

AF:

0.373

Gnomad OTH

AF:

0.432

GnomAD4 exome

AF:

0.289

AC:

AN:

194

Hom.:

Cov.:

AF XY:

0.304

AC XY:

AN XY:

show subpopulations

African (AFR)

AF:

1.00

AC:

AN:

American (AMR)

AF:

0.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AF:

0.500

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.299

AC:

AN:

174

Other (OTH)

AF:

0.500

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.429

AC:

65150

AN:

152032

Hom.:

14431

Cov.:

AF XY:

0.438

AC XY:

32581

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.498

AC:

20632

AN:

41464

American (AMR)

AF:

0.324

AC:

4945

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.437

AC:

1516

AN:

3472

East Asian (EAS)

AF:

0.589

AC:

3039

AN:

5158

South Asian (SAS)

AF:

0.513

AC:

2474

AN:

4824

European-Finnish (FIN)

AF:

0.546

AC:

5767

AN:

10564

Middle Eastern (MID)

AF:

0.395

AC:

116

AN:

294

European-Non Finnish (NFE)

AF:

0.373

AC:

25364

AN:

67974

Other (OTH)

AF:

0.435

AC:

916

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1877

3753

5630

7506

9383

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

618

1236

1854

2472

3090

<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:

0.255

Hom.:

608

Bravo

AF:

0.413

Asia WGS

AF:

0.523

AC:

1823

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.082

(source)

DANN

Benign

0.52

PhyloP100

-2.3

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

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