13-101143071-A-G

Variant names:

• chr13-101143071-A-G
• rs661585
• NM_052867.4:c.2118+9T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 13 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=-0.86).
• 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.
• 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 rank	MANE	Protein	UniProt
NALCN	NM_052867.4	c.2118+9T>C		intron_variant	Intron 17 of 43	ENST00000251127.11	NP_443099.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NALCN	ENST00000251127.11	c.2118+9T>C		intron_variant	Intron 17 of 43	1	NM_052867.4	ENSP00000251127.6

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

GnomAD2 exomes AF: 0.484 AC: 121599 AN: 251416 AF XY: 0.481

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 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

African (AFR) AF: 0.620 AC: 20744 AN: 33466

American (AMR) AF: 0.437 AC: 19535 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.468 AC: 12231 AN: 26132

East Asian (EAS) AF: 0.490 AC: 19452 AN: 39684

South Asian (SAS) AF: 0.532 AC: 45915 AN: 86236

European-Finnish (FIN) AF: 0.529 AC: 28245 AN: 53402

Middle Eastern (MID) AF: 0.447 AC: 2578 AN: 5766

European-Non Finnish (NFE) AF: 0.448 AC: 498351 AN: 1111712

Other (OTH) AF: 0.477 AC: 28784 AN: 60384

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

African (AFR) AF: 0.606 AC: 25114 AN: 41430

American (AMR) AF: 0.401 AC: 6127 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.468 AC: 1623 AN: 3468

East Asian (EAS) AF: 0.503 AC: 2598 AN: 5164

South Asian (SAS) AF: 0.547 AC: 2636 AN: 4822

European-Finnish (FIN) AF: 0.513 AC: 5416 AN: 10562

Middle Eastern (MID) AF: 0.446 AC: 131 AN: 294

European-Non Finnish (NFE) AF: 0.455 AC: 30895 AN: 67962

Other (OTH) AF: 0.481 AC: 1016 AN: 2114

Alfa AF: 0.469 Hom.: 54206

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Sep 05, 2021

Genome-Nilou Lab

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	-0.86
CADD	Benign	2.8
DANN	Benign	0.31
PhyloP100		-0.72
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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