rs661585

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_052867.4(NALCN):c.2118+9T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.466 in 1,613,500 control chromosomes in the GnomAD database, including 177,528 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.50 ( 19555 hom., cov: 32)

Exomes 𝑓: 0.46 ( 157973 hom. )

Consequence

NALCN
NM_052867.4 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.718

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 13-101143071-A-G is Benign according to our data. Variant chr13-101143071-A-G is described in ClinVar as [Benign]. Clinvar id is 262252.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-101143071-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.6 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NALCN	NM_052867.4 linkuse as main transcript	c.2118+9T>C		intron_variant		ENST00000251127.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NALCN	ENST00000251127.11 linkuse as main transcript	c.2118+9T>C		intron_variant		1	NM_052867.4	P1	Q8IZF0-1

Frequencies

GnomAD3 genomes

AF:

0.500

AC:

75923

AN:

151882

Hom.:

19526

Cov.:

show subpopulations

Gnomad AFR

AF:

0.606

Gnomad AMI

AF:

0.489

Gnomad AMR

AF:

0.401

Gnomad ASJ

AF:

0.468

Gnomad EAS

AF:

0.504

Gnomad SAS

AF:

0.547

Gnomad FIN

AF:

0.513

Gnomad MID

AF:

0.440

Gnomad NFE

AF:

0.455

Gnomad OTH

AF:

0.483

GnomAD3 exomes

AF:

0.484

AC:

121599

AN:

251416

Hom.:

29885

AF XY:

0.481

AC XY:

65410

AN XY:

135890

show subpopulations

Gnomad AFR exome

AF:

0.614

Gnomad AMR exome

AF:

0.437

Gnomad ASJ exome

AF:

0.474

Gnomad EAS exome

AF:

0.503

Gnomad SAS exome

AF:

0.537

Gnomad FIN exome

AF:

0.522

Gnomad NFE exome

AF:

0.456

Gnomad OTH exome

AF:

0.464

GnomAD4 exome

AF:

0.462

AC:

675835

AN:

1461500

Hom.:

157973

Cov.:

AF XY:

0.464

AC XY:

337467

AN XY:

727074

show subpopulations

Gnomad4 AFR exome

AF:

0.620

Gnomad4 AMR exome

AF:

0.437

Gnomad4 ASJ exome

AF:

0.468

Gnomad4 EAS exome

AF:

0.490

Gnomad4 SAS exome

AF:

0.532

Gnomad4 FIN exome

AF:

0.529

Gnomad4 NFE exome

AF:

0.448

Gnomad4 OTH exome

AF:

0.477

GnomAD4 genome

AF:

0.500

AC:

76000

AN:

152000

Hom.:

19555

Cov.:

AF XY:

0.501

AC XY:

37242

AN XY:

74302

show subpopulations

Gnomad4 AFR

AF:

0.606

Gnomad4 AMR

AF:

0.401

Gnomad4 ASJ

AF:

0.468

Gnomad4 EAS

AF:

0.503

Gnomad4 SAS

AF:

0.547

Gnomad4 FIN

AF:

0.513

Gnomad4 NFE

AF:

0.455

Gnomad4 OTH

AF:

0.481

Alfa

AF:

0.460

Hom.:

33644

Bravo

AF:

0.498

Asia WGS

AF:

0.543

AC:

1884

AN:

3478

EpiCase

AF:

0.447

EpiControl

AF:

0.442

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Hypotonia, infantile, with psychomotor retardation and characteristic facies 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

Cadd

Benign

2.8

Dann

Benign

0.31

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

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