rs9513851

Variant names:

• chr13-101095633-G-A
• rs9513851
• NM_052867.4:c.3210C>T

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.3210C>T​(p.Asn1070Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0645 in 1,611,716 control chromosomes in the GnomAD database, including 3,776 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.063 (332 hom., cov: 32)
  • Exomes 𝑓: 0.065 (3444 hom.)
• Consequence: NALCN NM_052867.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.39

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=-0.48).
• BP6: Variant 13-101095633-G-A is Benign according to our data. Variant chr13-101095633-G-A is described in ClinVar as [Benign]. Clinvar id is 262259.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.38 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.104 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NALCN	NM_052867.4	c.3210C>T	p.Asn1070Asn	synonymous_variant	Exon 28 of 44	ENST00000251127.11	NP_443099.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NALCN	ENST00000251127.11	c.3210C>T	p.Asn1070Asn	synonymous_variant	Exon 28 of 44	1	NM_052867.4	ENSP00000251127.6

Frequencies

GnomAD3 genomes AF: 0.0633 AC: 9608 AN: 151756 Hom.: 330 Cov.: 32

Gnomad AFR AF: 0.0742

Gnomad AMI AF: 0.0407

Gnomad AMR AF: 0.0489

Gnomad ASJ AF: 0.100

Gnomad EAS AF: 0.0340

Gnomad SAS AF: 0.112

Gnomad FIN AF: 0.0384

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.0612

Gnomad OTH AF: 0.0535

GnomAD3 exomes AF: 0.0627 AC: 15678 AN: 249948 Hom.: 625 AF XY: 0.0670 AC XY: 9056 AN XY: 135164

Gnomad AFR exome AF: 0.0706

Gnomad AMR exome AF: 0.0304

Gnomad ASJ exome AF: 0.0963

Gnomad EAS exome AF: 0.0375

Gnomad SAS exome AF: 0.113

Gnomad FIN exome AF: 0.0445

Gnomad NFE exome AF: 0.0624

Gnomad OTH exome AF: 0.0653

GnomAD4 exome AF: 0.0647 AC: 94412 AN: 1459842 Hom.: 3444 Cov.: 31 AF XY: 0.0666 AC XY: 48389 AN XY: 726226

Gnomad4 AFR exome AF: 0.0713

Gnomad4 AMR exome AF: 0.0317

Gnomad4 ASJ exome AF: 0.0945

Gnomad4 EAS exome AF: 0.0334

Gnomad4 SAS exome AF: 0.114

Gnomad4 FIN exome AF: 0.0473

Gnomad4 NFE exome AF: 0.0628

Gnomad4 OTH exome AF: 0.0692

GnomAD4 genome AF: 0.0633 AC: 9621 AN: 151874 Hom.: 332 Cov.: 32 AF XY: 0.0636 AC XY: 4719 AN XY: 74242

Gnomad4 AFR AF: 0.0742

Gnomad4 AMR AF: 0.0489

Gnomad4 ASJ AF: 0.100

Gnomad4 EAS AF: 0.0345

Gnomad4 SAS AF: 0.112

Gnomad4 FIN AF: 0.0384

Gnomad4 NFE AF: 0.0612

Gnomad4 OTH AF: 0.0529

Alfa AF: 0.0656 Hom.: 328

Bravo AF: 0.0626

Asia WGS AF: 0.0660 AC: 229 AN: 3478

EpiCase AF: 0.0631

EpiControl AF: 0.0644

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 15, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	4.7
DANN	Benign	0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs9513851; hg19: chr13-101747984; COSMIC: COSV51925834;