rs3916906

Positions:

• chr13-101229426-G-A
• chr13-101229426-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_052867.4(NALCN):​c.1593C>T​(p.Val531=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.335 in 1,602,124 control chromosomes in the GnomAD database, including 95,758 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V531V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.27 (6585 hom., cov: 33)
  • Exomes 𝑓: 0.34 (89173 hom.)
• Consequence: NALCN NM_052867.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.54

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 13-101229426-G-A is Benign according to our data. Variant chr13-101229426-G-A is described in ClinVar as [Benign]. Clinvar id is 262250.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-101229426-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.54 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.362 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NALCN	NM_052867.4	c.1593C>T	p.Val531=	synonymous_variant	13/44	ENST00000251127.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NALCN	ENST00000251127.11	c.1593C>T	p.Val531=	synonymous_variant	13/44	1	NM_052867.4	P1

Frequencies

GnomAD3 genomes AF: 0.271 AC: 41121 AN: 151930 Hom.: 6584 Cov.: 33

Gnomad AFR AF: 0.137

Gnomad AMI AF: 0.436

Gnomad AMR AF: 0.202

Gnomad ASJ AF: 0.289

Gnomad EAS AF: 0.0355

Gnomad SAS AF: 0.297

Gnomad FIN AF: 0.367

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.366

Gnomad OTH AF: 0.263

GnomAD3 exomes AF: 0.283 AC: 68633 AN: 242156 Hom.: 11302 AF XY: 0.293 AC XY: 38389 AN XY: 131080

Gnomad AFR exome AF: 0.135

Gnomad AMR exome AF: 0.146

Gnomad ASJ exome AF: 0.297

Gnomad EAS exome AF: 0.0370

Gnomad SAS exome AF: 0.309

Gnomad FIN exome AF: 0.365

Gnomad NFE exome AF: 0.359

Gnomad OTH exome AF: 0.299

GnomAD4 exome AF: 0.341 AC: 494986 AN: 1450078 Hom.: 89173 Cov.: 34 AF XY: 0.342 AC XY: 246460 AN XY: 721260

Gnomad4 AFR exome AF: 0.132

Gnomad4 AMR exome AF: 0.155

Gnomad4 ASJ exome AF: 0.296

Gnomad4 EAS exome AF: 0.0336

Gnomad4 SAS exome AF: 0.308

Gnomad4 FIN exome AF: 0.365

Gnomad4 NFE exome AF: 0.370

Gnomad4 OTH exome AF: 0.312

GnomAD4 genome AF: 0.270 AC: 41118 AN: 152046 Hom.: 6585 Cov.: 33 AF XY: 0.269 AC XY: 19973 AN XY: 74312

Gnomad4 AFR AF: 0.137

Gnomad4 AMR AF: 0.202

Gnomad4 ASJ AF: 0.289

Gnomad4 EAS AF: 0.0358

Gnomad4 SAS AF: 0.296

Gnomad4 FIN AF: 0.367

Gnomad4 NFE AF: 0.366

Gnomad4 OTH AF: 0.260

Alfa AF: 0.296 Hom.: 3369

Bravo AF: 0.252

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 15, 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

-

- -

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	-0.76
CADD	Benign	0.082
DANN	Benign	0.76

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

Other links and lift over

dbSNP: rs3916906; hg19: chr13-101881777; COSMIC: COSV51924498;