rs41281140

Variant names:

• chr13-101124603-G-A
• rs41281140
• NM_052867.4:c.2192+5C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001350748.2(NALCN):​c.2192+5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0119 in 1,611,668 control chromosomes in the GnomAD database, including 129 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0094 (2 hom., cov: 32)
  • Exomes 𝑓: 0.012 (127 hom.)
• Consequence: NALCN NM_001350748.2 splice_region, intron
• Scores: Splicing: ADA: 0.0001771
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.455
• Publications: 3 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=-0.73).
• BP6: Variant 13-101124603-G-A is Benign according to our data. Variant chr13-101124603-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262253.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00944 (1438/152260) while in subpopulation NFE AF = 0.0146 (996/68014). AF 95% confidence interval is 0.0139. There are 2 homozygotes in GnomAd4. There are 632 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001350748.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NALCN	NM_052867.4	MANE Select	c.2192+5C>T		splice_region intron	N/A	NP_443099.1
	NALCN	NM_001350748.2		c.2192+5C>T		splice_region intron	N/A	NP_001337677.1
	NALCN	NM_001350749.2		c.2192+5C>T		splice_region intron	N/A	NP_001337678.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NALCN	ENST00000251127.11	TSL:1 MANE Select	c.2192+5C>T		splice_region intron	N/A	ENSP00000251127.6
	NALCN	ENST00000675332.1		c.2192+5C>T		splice_region intron	N/A	ENSP00000501955.1
	NALCN	ENST00000858715.1		c.2192+5C>T		splice_region intron	N/A	ENSP00000528774.1

Frequencies

GnomAD3 genomes AF: 0.00945 AC: 1438 AN: 152142 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00270

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0105

Gnomad ASJ AF: 0.0199

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00594

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0146

Gnomad OTH AF: 0.0139

GnomAD2 exomes AF: 0.00870 AC: 2180 AN: 250566 AF XY: 0.00889

Gnomad AFR exome AF: 0.00228

Gnomad AMR exome AF: 0.00518

Gnomad ASJ exome AF: 0.0160

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00592

Gnomad NFE exome AF: 0.0138

Gnomad OTH exome AF: 0.0115

GnomAD4 exome AF: 0.0122 AC: 17805 AN: 1459408 Hom.: 127 Cov.: 29 AF XY: 0.0118 AC XY: 8534 AN XY: 726072

African (AFR) AF: 0.00201 AC: 67 AN: 33398

American (AMR) AF: 0.00622 AC: 277 AN: 44552

Ashkenazi Jewish (ASJ) AF: 0.0157 AC: 410 AN: 26094

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39664

South Asian (SAS) AF: 0.00122 AC: 105 AN: 85902

European-Finnish (FIN) AF: 0.00540 AC: 288 AN: 53370

Middle Eastern (MID) AF: 0.0141 AC: 81 AN: 5758

European-Non Finnish (NFE) AF: 0.0143 AC: 15880 AN: 1110332

Other (OTH) AF: 0.0115 AC: 694 AN: 60338

GnomAD4 genome AF: 0.00944 AC: 1438 AN: 152260 Hom.: 2 Cov.: 32 AF XY: 0.00849 AC XY: 632 AN XY: 74448

African (AFR) AF: 0.00270 AC: 112 AN: 41546

American (AMR) AF: 0.0105 AC: 160 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0199 AC: 69 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4822

European-Finnish (FIN) AF: 0.00594 AC: 63 AN: 10604

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0146 AC: 996 AN: 68014

Other (OTH) AF: 0.0137 AC: 29 AN: 2114

Alfa AF: 0.0122 Hom.: 27

Bravo AF: 0.00960

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0132

EpiControl AF: 0.0138

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	1	Hypotonia, infantile, with psychomotor retardation and characteristic facies 1;C4225398:Congenital contractures of the limbs and face, hypotonia, and developmental delay (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	11
DANN	Benign	0.64
PhyloP100		-0.46
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00018
dbscSNV1_RF	Benign	0.0040
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: rs41281140; hg19: chr13-101776954;