rs17582557

chr13-101176303-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_052867.4(NALCN):c.1836A>G(p.Lys612=) variant causes a synonymous change. The variant allele was found at a frequency of 0.0475 in 1,581,280 control chromosomes in the GnomAD database, including 2,031 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (151 hom., cov: 33)
  • Exomes 𝑓: 0.049 (1880 hom.)
• Consequence: NALCN NM_052867.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 5.10

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=-0.5).
• BP6: Variant 13-101176303-T-C is Benign according to our data. Variant chr13-101176303-T-C is described in ClinVar as [Benign]. Clinvar id is 262251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0515 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NALCN	NM_052867.4	c.1836A>G	p.Lys612=	synonymous_variant	15/44	ENST00000251127.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NALCN	ENST00000251127.11	c.1836A>G	p.Lys612=	synonymous_variant	15/44	1	NM_052867.4	P1

Frequencies

GnomAD3 genomes AF: 0.0374 AC: 5684 AN: 152162 Hom.: 151 Cov.: 33

Gnomad AFR AF: 0.00970

Gnomad AMI AF: 0.180

Gnomad AMR AF: 0.0300

Gnomad ASJ AF: 0.0620

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.0151

Gnomad FIN AF: 0.0639

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0530

Gnomad OTH AF: 0.0330

GnomAD3 exomes AF: 0.0429 AC: 9582 AN: 223590 Hom.: 263 AF XY: 0.0437 AC XY: 5317 AN XY: 121558

Gnomad AFR exome AF: 0.00776

Gnomad AMR exome AF: 0.0374

Gnomad ASJ exome AF: 0.0613

Gnomad EAS exome AF: 0.000315

Gnomad SAS exome AF: 0.0160

Gnomad FIN exome AF: 0.0668

Gnomad NFE exome AF: 0.0549

Gnomad OTH exome AF: 0.0577

GnomAD4 exome AF: 0.0486 AC: 69416 AN: 1428998 Hom.: 1880 Cov.: 30 AF XY: 0.0483 AC XY: 34312 AN XY: 710378

Gnomad4 AFR exome AF: 0.00690

Gnomad4 AMR exome AF: 0.0353

Gnomad4 ASJ exome AF: 0.0588

Gnomad4 EAS exome AF: 0.000186

Gnomad4 SAS exome AF: 0.0169

Gnomad4 FIN exome AF: 0.0624

Gnomad4 NFE exome AF: 0.0535

Gnomad4 OTH exome AF: 0.0446

GnomAD4 genome AF: 0.0373 AC: 5682 AN: 152282 Hom.: 151 Cov.: 33 AF XY: 0.0369 AC XY: 2750 AN XY: 74478

Gnomad4 AFR AF: 0.00967

Gnomad4 AMR AF: 0.0299

Gnomad4 ASJ AF: 0.0620

Gnomad4 EAS AF: 0.000965

Gnomad4 SAS AF: 0.0151

Gnomad4 FIN AF: 0.0639

Gnomad4 NFE AF: 0.0530

Gnomad4 OTH AF: 0.0326

Alfa AF: 0.0502 Hom.: 75

Bravo AF: 0.0343

Asia WGS AF: 0.0120 AC: 43 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 15, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	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	-0.50
Cadd	Benign	12
Dann	Benign	0.72

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: rs17582557; hg19: chr13-101828654; COSMIC: COSV51924490; COSMIC: COSV51924490;