13-101083724-A-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -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

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 262260.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-101083724-A-G is described in Lovd as [Benign].

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NALCN	NM_052867.4 link	c.3570T>C	p.Leu1190Leu	synonymous_variant	Exon 31 of 44	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.3570T>C	p.Leu1190Leu	synonymous_variant	Exon 31 of 44	1	NM_052867.4	ENSP00000251127.6		Q8IZF0-1

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

GnomAD3 exomes

AF:

0.687

AC:

172113

AN:

250546

Hom.:

61005

AF XY:

0.695

AC XY:

94058

AN XY:

135372

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 SAS exome

AF:

0.729

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

Gnomad4 AFR exome

AF:

0.852

Gnomad4 AMR exome

AF:

0.446

Gnomad4 ASJ exome

AF:

0.797

Gnomad4 EAS exome

AF:

0.580

Gnomad4 SAS exome

AF:

0.728

Gnomad4 FIN exome

AF:

0.723

Gnomad4 NFE exome

AF:

0.728

Gnomad4 OTH exome

AF:

0.726

GnomAD4 genome

AF:

0.740

AC:

112470

AN:

152078

Hom.:

42275

Cov.:

AF XY:

0.737

AC XY:

54787

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.842

Gnomad4 AMR

AF:

0.565

Gnomad4 ASJ

AF:

0.803

Gnomad4 EAS

AF:

0.604

Gnomad4 SAS

AF:

0.723

Gnomad4 FIN

AF:

0.738

Gnomad4 NFE

AF:

0.725

Gnomad4 OTH

AF:

0.733

Alfa

AF:

0.731

Hom.:

67561

Bravo

AF:

0.727

Asia WGS

AF:

0.664

AC:

2312

AN:

3478

EpiCase

AF:

0.725

EpiControl

AF:

0.724

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jul 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

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

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital contractures of the limbs and face, hypotonia, and developmental delay

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.56

CADD

Benign

6.9

DANN

Benign

0.70

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over