13-101376910-C-T

Position:

chr13-101376910-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_052867.4(NALCN):c.515+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0112 in 1,614,088 control chromosomes in the GnomAD database, including 130 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0089 ( 13 hom., cov: 33)

Exomes 𝑓: 0.011 ( 117 hom. )

Consequence

NALCN
NM_052867.4 splice_region, intron

Scores

Splicing: ADA: 0.00001276

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.689

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=-0.88).

BP6

Variant 13-101376910-C-T is Benign according to our data. Variant chr13-101376910-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 262265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00894 (1361/152280) while in subpopulation NFE AF= 0.0134 (914/68026). AF 95% confidence interval is 0.0127. There are 13 homozygotes in gnomad4. There are 641 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 13 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NALCN	NM_052867.4 linkuse as main transcript	c.515+7G>A		splice_region_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.515+7G>A		splice_region_variant, intron_variant		1	NM_052867.4	P1	Q8IZF0-1

Frequencies

GnomAD3 genomes

AF:

0.00896

AC:

1363

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00246

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00845

Gnomad ASJ

AF:

0.00433

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.0159

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0134

Gnomad OTH

AF:

0.0119

GnomAD3 exomes

AF:

0.00954

AC:

2397

AN:

251212

Hom.:

AF XY:

0.00942

AC XY:

1280

AN XY:

135842

show subpopulations

Gnomad AFR exome

AF:

0.00198

Gnomad AMR exome

AF:

0.00585

Gnomad ASJ exome

AF:

0.00476

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.00140

Gnomad FIN exome

AF:

0.0171

Gnomad NFE exome

AF:

0.0144

Gnomad OTH exome

AF:

0.0105

GnomAD4 exome

AF:

0.0114

AC:

16707

AN:

1461808

Hom.:

117

Cov.:

AF XY:

0.0111

AC XY:

8066

AN XY:

727204

show subpopulations

Gnomad4 AFR exome

AF:

0.00152

Gnomad4 AMR exome

AF:

0.00610

Gnomad4 ASJ exome

AF:

0.00467

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.00136

Gnomad4 FIN exome

AF:

0.0167

Gnomad4 NFE exome

AF:

0.0131

Gnomad4 OTH exome

AF:

0.00987

GnomAD4 genome

AF:

0.00894

AC:

1361

AN:

152280

Hom.:

Cov.:

AF XY:

0.00861

AC XY:

641

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.00245

Gnomad4 AMR

AF:

0.00837

Gnomad4 ASJ

AF:

0.00433

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.0159

Gnomad4 NFE

AF:

0.0134

Gnomad4 OTH

AF:

0.0118

Alfa

AF:

0.00909

Hom.:

Bravo

AF:

0.00822

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.0135

EpiControl

AF:

0.0139

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 26, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	NALCN: BP4, BS1, BS2 -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.82

DANN

Benign

0.45

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000013

dbscSNV1_RF

Benign

0.0

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