rs16958350

Variant summary

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

The NM_052867.4(NALCN):c.2637-10T>G variant causes a splice polypyrimidine tract, intron change. The variant allele was found at a frequency of 0.025 in 1,613,486 control chromosomes in the GnomAD database, including 680 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.027 ( 73 hom., cov: 33)

Exomes 𝑓: 0.025 ( 607 hom. )

Consequence

NALCN
NM_052867.4 splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.8343

Clinical Significance

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

Conservation

PhyloP100: 4.23

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=-0.6).

BP6

Variant 13-101104660-A-C is Benign according to our data. Variant chr13-101104660-A-C is described in ClinVar as [Benign]. Clinvar id is 262258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-101104660-A-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0634 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.2637-10T>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000251127.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NALCN	ENST00000251127.11 linkuse as main transcript	c.2637-10T>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_052867.4	P1	Q8IZF0-1

Frequencies

GnomAD3 genomes

AF:

0.0265

AC:

4036

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0360

Gnomad AMI

AF:

0.0263

Gnomad AMR

AF:

0.0175

Gnomad ASJ

AF:

0.0274

Gnomad EAS

AF:

0.0694

Gnomad SAS

AF:

0.0456

Gnomad FIN

AF:

0.00311

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0217

Gnomad OTH

AF:

0.0263

GnomAD3 exomes

AF:

0.0268

AC:

6703

AN:

250344

Hom.:

124

AF XY:

0.0278

AC XY:

3765

AN XY:

135258

show subpopulations

Gnomad AFR exome

AF:

0.0360

Gnomad AMR exome

AF:

0.0134

Gnomad ASJ exome

AF:

0.0277

Gnomad EAS exome

AF:

0.0701

Gnomad SAS exome

AF:

0.0458

Gnomad FIN exome

AF:

0.00421

Gnomad NFE exome

AF:

0.0217

Gnomad OTH exome

AF:

0.0261

GnomAD4 exome

AF:

0.0248

AC:

36218

AN:

1461228

Hom.:

607

Cov.:

AF XY:

0.0252

AC XY:

18305

AN XY:

726898

show subpopulations

Gnomad4 AFR exome

AF:

0.0357

Gnomad4 AMR exome

AF:

0.0140

Gnomad4 ASJ exome

AF:

0.0276

Gnomad4 EAS exome

AF:

0.0827

Gnomad4 SAS exome

AF:

0.0436

Gnomad4 FIN exome

AF:

0.00444

Gnomad4 NFE exome

AF:

0.0222

Gnomad4 OTH exome

AF:

0.0266

GnomAD4 genome

AF:

0.0266

AC:

4051

AN:

152258

Hom.:

Cov.:

AF XY:

0.0258

AC XY:

1919

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.0361

Gnomad4 AMR

AF:

0.0175

Gnomad4 ASJ

AF:

0.0274

Gnomad4 EAS

AF:

0.0694

Gnomad4 SAS

AF:

0.0465

Gnomad4 FIN

AF:

0.00311

Gnomad4 NFE

AF:

0.0217

Gnomad4 OTH

AF:

0.0279

Alfa

AF:

0.0245

Hom.:

Bravo

AF:

0.0270

Asia WGS

AF:

0.0680

AC:

238

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 03, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.60

Cadd

Benign

Dann

Benign

0.78

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.83

dbscSNV1_RF

Benign

0.68

SpliceAI score (max)

0.39

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.39

Position offset: -10

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