dbSNP rs34513106: NALCN:p.Val840Val (chr13-101107546-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_052867.4(NALCN):c.2520C>T(p.Val840Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00888 in 1,614,104 control chromosomes in the GnomAD database, including 124 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 20 hom., cov: 33)

Exomes 𝑓: 0.0084 ( 104 hom. )

Consequence

NALCN
NM_052867.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.372

Publications

4 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=-0.52).

BP6

Variant 13-101107546-G-A is Benign according to our data. Variant chr13-101107546-G-A is described in ClinVar as Benign. ClinVar VariationId is 262257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.372 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0132 (2015/152300) while in subpopulation AFR AF = 0.0272 (1130/41562). AF 95% confidence interval is 0.0259. There are 20 homozygotes in GnomAd4. There are 951 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 20 AD,AR gene

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	UniProt
NALCN	NM_052867.4	MANE Select	c.2520C>T	p.Val840Val	synonymous	Exon 22 of 44	NP_443099.1	Q8IZF0-1
NALCN	NM_001350748.2		c.2607C>T	p.Val869Val	synonymous	Exon 23 of 45	NP_001337677.1	A0A6Q8PFS9
NALCN	NM_001350749.2		c.2520C>T	p.Val840Val	synonymous	Exon 22 of 44	NP_001337678.1	Q8IZF0-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NALCN	ENST00000251127.11	TSL:1 MANE Select	c.2520C>T	p.Val840Val	synonymous	Exon 22 of 44	ENSP00000251127.6	Q8IZF0-1
NALCN	ENST00000675332.1		c.2607C>T	p.Val869Val	synonymous	Exon 23 of 45	ENSP00000501955.1	A0A6Q8PFS9
NALCN	ENST00000858715.1		c.2520C>T	p.Val840Val	synonymous	Exon 22 of 44	ENSP00000528774.1

Frequencies

GnomAD3 genomes

AF:

0.0132

AC:

2015

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0272

Gnomad AMI

AF:

0.0219

Gnomad AMR

AF:

0.0100

Gnomad ASJ

AF:

0.0181

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00932

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.00836

Gnomad OTH

AF:

0.00908

GnomAD2 exomes

AF:

0.00879

AC:

2208

AN:

251220

AF XY:

0.00880

show subpopulations

Gnomad AFR exome

AF:

0.0287

Gnomad AMR exome

AF:

0.00550

Gnomad ASJ exome

AF:

0.0216

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000370

Gnomad NFE exome

AF:

0.00841

Gnomad OTH exome

AF:

0.00816

GnomAD4 exome

AF:

0.00842

AC:

12314

AN:

1461804

Hom.:

104

Cov.:

AF XY:

0.00867

AC XY:

6302

AN XY:

727202

show subpopulations

African (AFR)

AF:

0.0271

AC:

908

AN:

33478

American (AMR)

AF:

0.00597

AC:

267

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.0214

AC:

560

AN:

26132

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39694

South Asian (SAS)

AF:

0.00998

AC:

861

AN:

86258

European-Finnish (FIN)

AF:

0.000693

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.0203

AC:

117

AN:

5768

European-Non Finnish (NFE)

AF:

0.00807

AC:

8970

AN:

1111960

Other (OTH)

AF:

0.00980

AC:

592

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

727

1454

2180

2907

3634

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

376

752

1128

1504

1880

<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:

0.0132

AC:

2015

AN:

152300

Hom.:

Cov.:

AF XY:

0.0128

AC XY:

951

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.0272

AC:

1130

AN:

41562

American (AMR)

AF:

0.0100

AC:

153

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0181

AC:

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5184

South Asian (SAS)

AF:

0.00933

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0374

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00838

AC:

570

AN:

68022

Other (OTH)

AF:

0.00899

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

103

206

310

413

516

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.0111

Hom.:

Bravo

AF:

0.0144

Asia WGS

AF:

0.00808

AC:

AN:

3478

EpiCase

AF:

0.0105

EpiControl

AF:

0.00990

ClinVar

ClinVar submissions

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

-0.52

CADD

Benign

0.18

(source)

DANN

Benign

0.69

PhyloP100

-0.37

Mutation Taster

=100/0

polymorphism

(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