13-101083724-A-G

Position:

• chr13-101083724-A-G

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.3570T>C​(p.Leu1190Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.721 in 1,612,644 control chromosomes in the GnomAD database, including 423,117 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.74 (42275 hom., cov: 32)
  • Exomes 𝑓: 0.72 (380842 hom.)
• Consequence: NALCN NM_052867.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.478

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=-0.56).
• BP6: Variant 13-101083724-A-G is Benign according to our data. Variant chr13-101083724-A-G is described in ClinVar as [Benign]. Clinvar id is 262260.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-101083724-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.478 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.835 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NALCN	NM_052867.4	c.3570T>C	p.Leu1190Leu	synonymous_variant	31/44	ENST00000251127.11	NP_443099.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NALCN	ENST00000251127.11	c.3570T>C	p.Leu1190Leu	synonymous_variant	31/44	1	NM_052867.4	ENSP00000251127.6

Frequencies

GnomAD3 genomes AF: 0.740 AC: 112388 AN: 151960 Hom.: 42240 Cov.: 32

Gnomad AFR AF: 0.842

Gnomad AMI AF: 0.775

Gnomad AMR AF: 0.565

Gnomad ASJ AF: 0.803

Gnomad EAS AF: 0.604

Gnomad SAS AF: 0.725

Gnomad FIN AF: 0.738

Gnomad MID AF: 0.684

Gnomad NFE AF: 0.725

Gnomad OTH AF: 0.733

GnomAD3 exomes AF: 0.687 AC: 172113 AN: 250546 Hom.: 61005 AF XY: 0.695 AC XY: 94058 AN XY: 135372

Gnomad AFR exome AF: 0.850

Gnomad AMR exome AF: 0.431

Gnomad ASJ exome AF: 0.793

Gnomad EAS exome AF: 0.607

Gnomad SAS exome AF: 0.729

Gnomad FIN exome AF: 0.724

Gnomad NFE exome AF: 0.726

Gnomad OTH exome AF: 0.693

GnomAD4 exome AF: 0.719 AC: 1050220 AN: 1460566 Hom.: 380842 Cov.: 46 AF XY: 0.720 AC XY: 523026 AN XY: 726438

Gnomad4 AFR exome AF: 0.852

Gnomad4 AMR exome AF: 0.446

Gnomad4 ASJ exome AF: 0.797

Gnomad4 EAS exome AF: 0.580

Gnomad4 SAS exome AF: 0.728

Gnomad4 FIN exome AF: 0.723

Gnomad4 NFE exome AF: 0.728

Gnomad4 OTH exome AF: 0.726

GnomAD4 genome AF: 0.740 AC: 112470 AN: 152078 Hom.: 42275 Cov.: 32 AF XY: 0.737 AC XY: 54787 AN XY: 74334

Gnomad4 AFR AF: 0.842

Gnomad4 AMR AF: 0.565

Gnomad4 ASJ AF: 0.803

Gnomad4 EAS AF: 0.604

Gnomad4 SAS AF: 0.723

Gnomad4 FIN AF: 0.738

Gnomad4 NFE AF: 0.725

Gnomad4 OTH AF: 0.733

Alfa AF: 0.731 Hom.: 67561

Bravo AF: 0.727

Asia WGS AF: 0.664 AC: 2312 AN: 3478

EpiCase AF: 0.725

EpiControl AF: 0.724

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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	-0.56
CADD	Benign	6.9
DANN	Benign	0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs686141; hg19: chr13-101736075; COSMIC: COSV51915224;