rs79264337

chr13-101111178-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_052867.4(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 NM_052867.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -4.83

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=-0.75).
• 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 GnomAd at 2 AD,AR gene

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00493 AC: 750 AN: 152046 Hom.: 2 Cov.: 32

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.: 1 AF XY: 0.00272 AC XY: 368 AN XY: 135466

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.: 10 Cov.: 31 AF XY: 0.00340 AC XY: 2463 AN XY: 723538

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.: 2 Cov.: 32 AF XY: 0.00457 AC XY: 340 AN XY: 74384

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.: 1

Bravo AF: 0.00532

Asia WGS AF: 0.00144 AC: 5 AN: 3476

EpiCase AF: 0.00404

EpiControl AF: 0.00350

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 05, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	- -

NALCN-related disorder Benign:1

Benign, criteria provided, single submitter

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

Other links and lift over

dbSNP: rs79264337; hg19: chr13-101763529; COSMIC: COSV51959387;