NM_052867.4:c.515+7G>A

Variant names:

• chr13-101376910-C-T
• rs41281142
• NM_052867.4:c.515+7G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_052867.4(NALCN):​c.515+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0112 in 1,614,088 control chromosomes in the GnomAD database, including 130 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0089 (13 hom., cov: 33)
  • Exomes 𝑓: 0.011 (117 hom.)
• Consequence: NALCN NM_052867.4 splice_region, intron
• Scores: Splicing: ADA: 0.00001276
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.689
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 13-101376910-C-T is Benign according to our data. Variant chr13-101376910-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00894 (1361/152280) while in subpopulation NFE AF = 0.0134 (914/68026). AF 95% confidence interval is 0.0127. There are 13 homozygotes in GnomAd4. There are 641 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 AD,AR gene

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.515+7G>A		splice_region intron	N/A	NP_443099.1	Q8IZF0-1
	NALCN	NM_001350748.2		c.515+7G>A		splice_region intron	N/A	NP_001337677.1	A0A6Q8PFS9
	NALCN	NM_001350749.2		c.515+7G>A		splice_region intron	N/A	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.515+7G>A		splice_region intron	N/A	ENSP00000251127.6	Q8IZF0-1
	NALCN	ENST00000376200.6	TSL:1	c.515+7G>A		splice_region intron	N/A	ENSP00000365373.5	Q8IZF0-3
	NALCN	ENST00000470333.1	TSL:1	n.611+7G>A		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00896 AC: 1363 AN: 152162 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.00246

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00845

Gnomad ASJ AF: 0.00433

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0159

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0134

Gnomad OTH AF: 0.0119

GnomAD2 exomes AF: 0.00954 AC: 2397 AN: 251212 AF XY: 0.00942

Gnomad AFR exome AF: 0.00198

Gnomad AMR exome AF: 0.00585

Gnomad ASJ exome AF: 0.00476

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0171

Gnomad NFE exome AF: 0.0144

Gnomad OTH exome AF: 0.0105

GnomAD4 exome AF: 0.0114 AC: 16707 AN: 1461808 Hom.: 117 Cov.: 31 AF XY: 0.0111 AC XY: 8066 AN XY: 727204

African (AFR) AF: 0.00152 AC: 51 AN: 33480

American (AMR) AF: 0.00610 AC: 273 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00467 AC: 122 AN: 26134

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39684

South Asian (SAS) AF: 0.00136 AC: 117 AN: 86248

European-Finnish (FIN) AF: 0.0167 AC: 893 AN: 53416

Middle Eastern (MID) AF: 0.0158 AC: 91 AN: 5768

European-Non Finnish (NFE) AF: 0.0131 AC: 14558 AN: 1111974

Other (OTH) AF: 0.00987 AC: 596 AN: 60386

GnomAD4 genome AF: 0.00894 AC: 1361 AN: 152280 Hom.: 13 Cov.: 33 AF XY: 0.00861 AC XY: 641 AN XY: 74452

African (AFR) AF: 0.00245 AC: 102 AN: 41556

American (AMR) AF: 0.00837 AC: 128 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00433 AC: 15 AN: 3466

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4830

European-Finnish (FIN) AF: 0.0159 AC: 169 AN: 10600

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0134 AC: 914 AN: 68026

Other (OTH) AF: 0.0118 AC: 25 AN: 2116

Alfa AF: 0.00908 Hom.: 6

Bravo AF: 0.00822

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0135

EpiControl AF: 0.0139

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.82
DANN	Benign	0.45
PhyloP100		-0.69
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000013
dbscSNV1_RF	Benign	0.0
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

Other links and lift over

dbSNP: rs41281142; hg19: chr13-102029261; COSMIC: COSV51926298;