rs661585

Positions:

• chr13-101143071-A-G

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.2118+9T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.466 in 1,613,500 control chromosomes in the GnomAD database, including 177,528 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.50 (19555 hom., cov: 32)
  • Exomes 𝑓: 0.46 (157973 hom.)
• Consequence: NALCN NM_052867.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.718

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=-0.86).
• BP6: Variant 13-101143071-A-G is Benign according to our data. Variant chr13-101143071-A-G is described in ClinVar as [Benign]. Clinvar id is 262252.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-101143071-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.6 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NALCN	NM_052867.4	c.2118+9T>C		intron_variant		ENST00000251127.11	NP_443099.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NALCN	ENST00000251127.11	c.2118+9T>C		intron_variant		1	NM_052867.4	ENSP00000251127	P1

Frequencies

GnomAD3 genomes AF: 0.500 AC: 75923 AN: 151882 Hom.: 19526 Cov.: 32

Gnomad AFR AF: 0.606

Gnomad AMI AF: 0.489

Gnomad AMR AF: 0.401

Gnomad ASJ AF: 0.468

Gnomad EAS AF: 0.504

Gnomad SAS AF: 0.547

Gnomad FIN AF: 0.513

Gnomad MID AF: 0.440

Gnomad NFE AF: 0.455

Gnomad OTH AF: 0.483

GnomAD3 exomes AF: 0.484 AC: 121599 AN: 251416 Hom.: 29885 AF XY: 0.481 AC XY: 65410 AN XY: 135890

Gnomad AFR exome AF: 0.614

Gnomad AMR exome AF: 0.437

Gnomad ASJ exome AF: 0.474

Gnomad EAS exome AF: 0.503

Gnomad SAS exome AF: 0.537

Gnomad FIN exome AF: 0.522

Gnomad NFE exome AF: 0.456

Gnomad OTH exome AF: 0.464

GnomAD4 exome AF: 0.462 AC: 675835 AN: 1461500 Hom.: 157973 Cov.: 42 AF XY: 0.464 AC XY: 337467 AN XY: 727074

Gnomad4 AFR exome AF: 0.620

Gnomad4 AMR exome AF: 0.437

Gnomad4 ASJ exome AF: 0.468

Gnomad4 EAS exome AF: 0.490

Gnomad4 SAS exome AF: 0.532

Gnomad4 FIN exome AF: 0.529

Gnomad4 NFE exome AF: 0.448

Gnomad4 OTH exome AF: 0.477

GnomAD4 genome AF: 0.500 AC: 76000 AN: 152000 Hom.: 19555 Cov.: 32 AF XY: 0.501 AC XY: 37242 AN XY: 74302

Gnomad4 AFR AF: 0.606

Gnomad4 AMR AF: 0.401

Gnomad4 ASJ AF: 0.468

Gnomad4 EAS AF: 0.503

Gnomad4 SAS AF: 0.547

Gnomad4 FIN AF: 0.513

Gnomad4 NFE AF: 0.455

Gnomad4 OTH AF: 0.481

Alfa AF: 0.460 Hom.: 33644

Bravo AF: 0.498

Asia WGS AF: 0.543 AC: 1884 AN: 3478

EpiCase AF: 0.447

EpiControl AF: 0.442

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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

-

- -

Hypotonia, infantile, with psychomotor retardation and characteristic facies 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Congenital contractures of the limbs and face, hypotonia, and developmental delay Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.8
DANN	Benign	0.31

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: rs661585; hg19: chr13-101795422; COSMIC: COSV51923065;