chr13-101376910-C-T

Position:

• chr13-101376910-C-T

Variant summary

Our verdict is Benign. Variant got -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

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 -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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 13 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NALCN	NM_052867.4	c.515+7G>A		splice_region_variant, intron_variant		ENST00000251127.11	NP_443099.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NALCN	ENST00000251127.11	c.515+7G>A		splice_region_variant, intron_variant		1	NM_052867.4	ENSP00000251127	P1

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

GnomAD3 exomes AF: 0.00954 AC: 2397 AN: 251212 Hom.: 28 AF XY: 0.00942 AC XY: 1280 AN XY: 135842

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 SAS exome AF: 0.00140

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

Gnomad4 AFR exome AF: 0.00152

Gnomad4 AMR exome AF: 0.00610

Gnomad4 ASJ exome AF: 0.00467

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.00136

Gnomad4 FIN exome AF: 0.0167

Gnomad4 NFE exome AF: 0.0131

Gnomad4 OTH exome AF: 0.00987

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

Gnomad4 AFR AF: 0.00245

Gnomad4 AMR AF: 0.00837

Gnomad4 ASJ AF: 0.00433

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.0159

Gnomad4 NFE AF: 0.0134

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.00909 Hom.: 6

Bravo AF: 0.00822

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0135

EpiControl AF: 0.0139

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	NALCN: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 26, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.82
DANN	Benign	0.45

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

Publications

LitVar

Other links and lift over

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