chr13-101104660-A-C

Variant names:

• chr13-101104660-A-C
• rs16958350
• NM_052867.4:c.2637-10T>G

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.2637-10T>G variant causes a intron change. The variant allele was found at a frequency of 0.025 in 1,613,486 control chromosomes in the GnomAD database, including 680 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (73 hom., cov: 33)
  • Exomes 𝑓: 0.025 (607 hom.)
• Consequence: NALCN NM_052867.4 intron
• Scores: Splicing: ADA: 0.8343
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 4.23
• Publications: 4 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=-0.6).
• BP6: Variant 13-101104660-A-C is Benign according to our data. Variant chr13-101104660-A-C is described in ClinVar as Benign. ClinVar VariationId is 262258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0634 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_052867.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NALCN	NM_052867.4	MANE Select	c.2637-10T>G		intron	N/A	NP_443099.1
	NALCN	NM_001350748.2		c.2724-10T>G		intron	N/A	NP_001337677.1
	NALCN	NM_001350749.2		c.2637-10T>G		intron	N/A	NP_001337678.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NALCN	ENST00000251127.11	TSL:1 MANE Select	c.2637-10T>G		intron	N/A	ENSP00000251127.6
	NALCN	ENST00000675332.1		c.2724-10T>G		intron	N/A	ENSP00000501955.1
	NALCN	ENST00000676315.1		c.2550-10T>G		intron	N/A	ENSP00000501603.1

Frequencies

GnomAD3 genomes AF: 0.0265 AC: 4036 AN: 152140 Hom.: 70 Cov.: 33

Gnomad AFR AF: 0.0360

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.0175

Gnomad ASJ AF: 0.0274

Gnomad EAS AF: 0.0694

Gnomad SAS AF: 0.0456

Gnomad FIN AF: 0.00311

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0217

Gnomad OTH AF: 0.0263

GnomAD2 exomes AF: 0.0268 AC: 6703 AN: 250344 AF XY: 0.0278

Gnomad AFR exome AF: 0.0360

Gnomad AMR exome AF: 0.0134

Gnomad ASJ exome AF: 0.0277

Gnomad EAS exome AF: 0.0701

Gnomad FIN exome AF: 0.00421

Gnomad NFE exome AF: 0.0217

Gnomad OTH exome AF: 0.0261

GnomAD4 exome AF: 0.0248 AC: 36218 AN: 1461228 Hom.: 607 Cov.: 31 AF XY: 0.0252 AC XY: 18305 AN XY: 726898

African (AFR) AF: 0.0357 AC: 1194 AN: 33450

American (AMR) AF: 0.0140 AC: 627 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.0276 AC: 721 AN: 26108

East Asian (EAS) AF: 0.0827 AC: 3277 AN: 39620

South Asian (SAS) AF: 0.0436 AC: 3759 AN: 86176

European-Finnish (FIN) AF: 0.00444 AC: 237 AN: 53410

Middle Eastern (MID) AF: 0.0229 AC: 132 AN: 5758

European-Non Finnish (NFE) AF: 0.0222 AC: 24667 AN: 1111638

Other (OTH) AF: 0.0266 AC: 1604 AN: 60370

GnomAD4 genome AF: 0.0266 AC: 4051 AN: 152258 Hom.: 73 Cov.: 33 AF XY: 0.0258 AC XY: 1919 AN XY: 74456

African (AFR) AF: 0.0361 AC: 1499 AN: 41552

American (AMR) AF: 0.0175 AC: 268 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0274 AC: 95 AN: 3472

East Asian (EAS) AF: 0.0694 AC: 359 AN: 5176

South Asian (SAS) AF: 0.0465 AC: 224 AN: 4816

European-Finnish (FIN) AF: 0.00311 AC: 33 AN: 10620

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0217 AC: 1479 AN: 68006

Other (OTH) AF: 0.0279 AC: 59 AN: 2116

Alfa AF: 0.0247 Hom.: 118

Bravo AF: 0.0270

Asia WGS AF: 0.0680 AC: 238 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 03, 2018

GeneDx

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

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

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	14
DANN	Benign	0.78
PhyloP100		4.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.83
dbscSNV1_RF	Benign	0.68
SpliceAI score (max)		0.39		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.39		Position offset: -10

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs16958350; hg19: chr13-101757011; COSMIC: COSV51954690;