rs79264337

Positions:

chr13-101111178-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The ENST00000251127.11(NALCN):c.2241C>T(p.Pro747=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00371 in 1,608,526 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0049 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0036 ( 10 hom. )

Consequence

NALCN
ENST00000251127.11 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -4.83

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=-0.75).

BP6

Variant 13-101111178-G-A is Benign according to our data. Variant chr13-101111178-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 262254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-101111178-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-4.83 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00494 (751/152164) while in subpopulation AFR AF= 0.0104 (430/41518). AF 95% confidence interval is 0.00955. There are 2 homozygotes in gnomad4. There are 340 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NALCN	NM_052867.4 linkuse as main transcript	c.2241C>T	p.Pro747=	synonymous_variant	19/44	ENST00000251127.11	NP_443099.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NALCN	ENST00000251127.11 linkuse as main transcript	c.2241C>T	p.Pro747=	synonymous_variant	19/44	1	NM_052867.4	ENSP00000251127	P1	Q8IZF0-1

Frequencies

GnomAD3 genomes

AF:

0.00493

AC:

750

AN:

152046

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0104

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00256

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00113

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00382

Gnomad OTH

AF:

0.00336

GnomAD3 exomes

AF:

0.00277

AC:

693

AN:

250570

Hom.:

AF XY:

0.00272

AC XY:

368

AN XY:

135466

show subpopulations

Gnomad AFR exome

AF:

0.00954

Gnomad AMR exome

AF:

0.00194

Gnomad ASJ exome

AF:

0.000795

Gnomad EAS exome

AF:

0.000272

Gnomad SAS exome

AF:

0.000294

Gnomad FIN exome

AF:

0.000754

Gnomad NFE exome

AF:

0.00362

Gnomad OTH exome

AF:

0.00376

GnomAD4 exome

AF:

0.00359

AC:

5223

AN:

1456362

Hom.:

Cov.:

AF XY:

0.00340

AC XY:

2463

AN XY:

723538

show subpopulations

Gnomad4 AFR exome

AF:

0.00984

Gnomad4 AMR exome

AF:

0.00213

Gnomad4 ASJ exome

AF:

0.000690

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.000372

Gnomad4 FIN exome

AF:

0.000871

Gnomad4 NFE exome

AF:

0.00398

Gnomad4 OTH exome

AF:

0.00452

GnomAD4 genome

AF:

0.00494

AC:

751

AN:

152164

Hom.:

Cov.:

AF XY:

0.00457

AC XY:

340

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.0104

Gnomad4 AMR

AF:

0.00255

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00113

Gnomad4 NFE

AF:

0.00382

Gnomad4 OTH

AF:

0.00332

Alfa

AF:

0.00369

Hom.:

Bravo

AF:

0.00532

Asia WGS

AF:

0.00144

AC:

AN:

3476

EpiCase

AF:

0.00404

EpiControl

AF:

0.00350

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	NALCN: BP4, BP7, BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 05, 2018	- -

NALCN-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 05, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hypotonia, infantile, with psychomotor retardation and characteristic facies 1;C4225398:Congenital contractures of the limbs and face, hypotonia, and developmental delay

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 22, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.11

DANN

Benign

0.80

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