13-101083724-A-G

Variant names:

• chr13-101083724-A-G
• rs686141
• NM_052867.4:c.3570T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 19 publications found

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 Gene-Disease associations (from GenCC):

• congenital contractures of the limbs and face, hypotonia, and developmental delay

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• hypotonia, infantile, with psychomotor retardation and characteristic facies 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• digitotalar dysmorphism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Freeman-Sheldon syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Sheldon-hall syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hypotonia, infantile, with psychomotor retardation and characteristic facies

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• temporal lobe epilepsy

  Inheritance: AD Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 262260.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_052867.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NALCN	NM_052867.4	MANE Select	c.3570T>C	p.Leu1190Leu	synonymous	Exon 31 of 44	NP_443099.1	Q8IZF0-1
	NALCN	NM_001350748.2		c.3657T>C	p.Leu1219Leu	synonymous	Exon 32 of 45	NP_001337677.1	A0A6Q8PFS9
	NALCN	NM_001350749.2		c.3570T>C	p.Leu1190Leu	synonymous	Exon 31 of 44	NP_001337678.1	Q8IZF0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NALCN	ENST00000251127.11	TSL:1 MANE Select	c.3570T>C	p.Leu1190Leu	synonymous	Exon 31 of 44	ENSP00000251127.6	Q8IZF0-1
	NALCN	ENST00000675332.1		c.3657T>C	p.Leu1219Leu	synonymous	Exon 32 of 45	ENSP00000501955.1	A0A6Q8PFS9
	NALCN	ENST00000858715.1		c.3570T>C	p.Leu1190Leu	synonymous	Exon 31 of 44	ENSP00000528774.1

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

GnomAD2 exomes AF: 0.687 AC: 172113 AN: 250546 AF XY: 0.695

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 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

African (AFR) AF: 0.852 AC: 28528 AN: 33464

American (AMR) AF: 0.446 AC: 19928 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.797 AC: 20822 AN: 26122

East Asian (EAS) AF: 0.580 AC: 23014 AN: 39646

South Asian (SAS) AF: 0.728 AC: 62728 AN: 86158

European-Finnish (FIN) AF: 0.723 AC: 38596 AN: 53360

Middle Eastern (MID) AF: 0.714 AC: 4116 AN: 5762

European-Non Finnish (NFE) AF: 0.728 AC: 808688 AN: 1111044

Other (OTH) AF: 0.726 AC: 43800 AN: 60332

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

African (AFR) AF: 0.842 AC: 34937 AN: 41486

American (AMR) AF: 0.565 AC: 8626 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.803 AC: 2784 AN: 3468

East Asian (EAS) AF: 0.604 AC: 3119 AN: 5160

South Asian (SAS) AF: 0.723 AC: 3480 AN: 4812

European-Finnish (FIN) AF: 0.738 AC: 7809 AN: 10576

Middle Eastern (MID) AF: 0.677 AC: 199 AN: 294

European-Non Finnish (NFE) AF: 0.725 AC: 49260 AN: 67980

Other (OTH) AF: 0.733 AC: 1549 AN: 2112

Alfa AF: 0.730 Hom.: 81359

Bravo AF: 0.727

Asia WGS AF: 0.664 AC: 2312 AN: 3478

EpiCase AF: 0.725

EpiControl AF: 0.724

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Congenital contractures of the limbs and face, hypotonia, and developmental delay (1)
-	-	1	Hypotonia, infantile, with psychomotor retardation and characteristic facies 1 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	6.9
DANN	Benign	0.70
PhyloP100		0.48
Mutation Taster		=93/7	polymorphism (auto)

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

Other links and lift over

dbSNP: rs686141; hg19: chr13-101736075; COSMIC: COSV51915224;