Genetic Variant NM_052867.4:c.3570T>C (chr13-101083724-A-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_052867.4(NALCN):c.3570T>C(p.Leu1190Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.721 in 1,612,644 control chromosomes in the GnomAD database, including 423,117 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.74 ( 42275 hom., cov: 32)

Exomes 𝑓: 0.72 ( 380842 hom. )

Consequence

NALCN
NM_052867.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.478

Publications

19 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=-0.56).

BP6

Variant 13-101083724-A-G is Benign according to our data. Variant chr13-101083724-A-G is described in ClinVar as Benign. ClinVar VariationId is 262260.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.478 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.835 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	UniProt
NALCN	NM_052867.4	MANE Select	c.3570T>C	p.Leu1190Leu	synonymous	Exon 31 of 44	NP_443099.1	Q8IZF0-1
NALCN	NM_001350748.2		c.3657T>C	p.Leu1219Leu	synonymous	Exon 32 of 45	NP_001337677.1	A0A6Q8PFS9
NALCN	NM_001350749.2		c.3570T>C	p.Leu1190Leu	synonymous	Exon 31 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.3570T>C	p.Leu1190Leu	synonymous	Exon 31 of 44	ENSP00000251127.6	Q8IZF0-1
NALCN	ENST00000675332.1		c.3657T>C	p.Leu1219Leu	synonymous	Exon 32 of 45	ENSP00000501955.1	A0A6Q8PFS9
NALCN	ENST00000858715.1		c.3570T>C	p.Leu1190Leu	synonymous	Exon 31 of 44	ENSP00000528774.1

Frequencies

GnomAD3 genomes

AF:

0.740

AC:

112388

AN:

151960

Hom.:

42240

Cov.:

show subpopulations

Gnomad AFR

AF:

0.842

Gnomad AMI

AF:

0.775

Gnomad AMR

AF:

0.565

Gnomad ASJ

AF:

0.803

Gnomad EAS

AF:

0.604

Gnomad SAS

AF:

0.725

Gnomad FIN

AF:

0.738

Gnomad MID

AF:

0.684

Gnomad NFE

AF:

0.725

Gnomad OTH

AF:

0.733

GnomAD2 exomes

AF:

0.687

AC:

172113

AN:

250546

AF XY:

0.695

show subpopulations

Gnomad AFR exome

AF:

0.850

Gnomad AMR exome

AF:

0.431

Gnomad ASJ exome

AF:

0.793

Gnomad EAS exome

AF:

0.607

Gnomad FIN exome

AF:

0.724

Gnomad NFE exome

AF:

0.726

Gnomad OTH exome

AF:

0.693

GnomAD4 exome

AF:

0.719

AC:

1050220

AN:

1460566

Hom.:

380842

Cov.:

AF XY:

0.720

AC XY:

523026

AN XY:

726438

show subpopulations

African (AFR)

AF:

0.852

AC:

28528

AN:

33464

American (AMR)

AF:

0.446

AC:

19928

AN:

44678

Ashkenazi Jewish (ASJ)

AF:

0.797

AC:

20822

AN:

26122

East Asian (EAS)

AF:

0.580

AC:

23014

AN:

39646

South Asian (SAS)

AF:

0.728

AC:

62728

AN:

86158

European-Finnish (FIN)

AF:

0.723

AC:

38596

AN:

53360

Middle Eastern (MID)

AF:

0.714

AC:

4116

AN:

5762

European-Non Finnish (NFE)

AF:

0.728

AC:

808688

AN:

1111044

Other (OTH)

AF:

0.726

AC:

43800

AN:

60332

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

13715

27430

41146

54861

68576

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19976

39952

59928

79904

99880

<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:

0.740

AC:

112470

AN:

152078

Hom.:

42275

Cov.:

AF XY:

0.737

AC XY:

54787

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.842

AC:

34937

AN:

41486

American (AMR)

AF:

0.565

AC:

8626

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.803

AC:

2784

AN:

3468

East Asian (EAS)

AF:

0.604

AC:

3119

AN:

5160

South Asian (SAS)

AF:

0.723

AC:

3480

AN:

4812

European-Finnish (FIN)

AF:

0.738

AC:

7809

AN:

10576

Middle Eastern (MID)

AF:

0.677

AC:

199

AN:

294

European-Non Finnish (NFE)

AF:

0.725

AC:

49260

AN:

67980

Other (OTH)

AF:

0.733

AC:

1549

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1436

2871

4307

5742

7178

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

844

1688

2532

3376

4220

<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:

0.730

Hom.:

81359

Bravo

AF:

0.727

Asia WGS

AF:

0.664

AC:

2312

AN:

3478

EpiCase

AF:

0.725

EpiControl

AF:

0.724

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

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

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

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.56

CADD

Benign

6.9

(source)

DANN

Benign

0.70

PhyloP100

0.48

Mutation Taster

=93/7

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Computational scores

Splicing

Publications

Other links and lift over