rs3916906

Variant names:

• chr13-101229426-G-A
• rs3916906
• NM_052867.4:c.1593C>T

Your query was ambiguous. Multiple possible variants found:

• chr13-101229426-G-A
• chr13-101229426-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_052867.4(NALCN):​c.1593C>T​(p.Val531Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.335 in 1,602,124 control chromosomes in the GnomAD database, including 95,758 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V531V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.27 (6585 hom., cov: 33)
  • Exomes 𝑓: 0.34 (89173 hom.)
• Consequence: NALCN NM_052867.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.54
• Publications: 16 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 13-101229426-G-A is Benign according to our data. Variant chr13-101229426-G-A is described in ClinVar as Benign. ClinVar VariationId is 262250.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.54 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.362 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NALCN	NM_052867.4	MANE Select	c.1593C>T	p.Val531Val	synonymous	Exon 13 of 44	NP_443099.1	Q8IZF0-1
	NALCN	NM_001350748.2		c.1593C>T	p.Val531Val	synonymous	Exon 13 of 45	NP_001337677.1	A0A6Q8PFS9
	NALCN	NM_001350749.2		c.1593C>T	p.Val531Val	synonymous	Exon 13 of 44	NP_001337678.1	Q8IZF0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NALCN	ENST00000251127.11	TSL:1 MANE Select	c.1593C>T	p.Val531Val	synonymous	Exon 13 of 44	ENSP00000251127.6	Q8IZF0-1
	NALCN	ENST00000470333.1	TSL:1	n.1689C>T		non_coding_transcript_exon	Exon 13 of 15
	NALCN	ENST00000675332.1		c.1593C>T	p.Val531Val	synonymous	Exon 13 of 45	ENSP00000501955.1	A0A6Q8PFS9

Frequencies

GnomAD3 genomes AF: 0.271 AC: 41121 AN: 151930 Hom.: 6584 Cov.: 33

Gnomad AFR AF: 0.137

Gnomad AMI AF: 0.436

Gnomad AMR AF: 0.202

Gnomad ASJ AF: 0.289

Gnomad EAS AF: 0.0355

Gnomad SAS AF: 0.297

Gnomad FIN AF: 0.367

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.366

Gnomad OTH AF: 0.263

GnomAD2 exomes AF: 0.283 AC: 68633 AN: 242156 AF XY: 0.293

Gnomad AFR exome AF: 0.135

Gnomad AMR exome AF: 0.146

Gnomad ASJ exome AF: 0.297

Gnomad EAS exome AF: 0.0370

Gnomad FIN exome AF: 0.365

Gnomad NFE exome AF: 0.359

Gnomad OTH exome AF: 0.299

GnomAD4 exome AF: 0.341 AC: 494986 AN: 1450078 Hom.: 89173 Cov.: 34 AF XY: 0.342 AC XY: 246460 AN XY: 721260

African (AFR) AF: 0.132 AC: 4370 AN: 32994

American (AMR) AF: 0.155 AC: 6610 AN: 42574

Ashkenazi Jewish (ASJ) AF: 0.296 AC: 7677 AN: 25924

East Asian (EAS) AF: 0.0336 AC: 1303 AN: 38830

South Asian (SAS) AF: 0.308 AC: 25901 AN: 84172

European-Finnish (FIN) AF: 0.365 AC: 19391 AN: 53094

Middle Eastern (MID) AF: 0.213 AC: 1224 AN: 5738

European-Non Finnish (NFE) AF: 0.370 AC: 409858 AN: 1106890

Other (OTH) AF: 0.312 AC: 18652 AN: 59862

GnomAD4 genome AF: 0.270 AC: 41118 AN: 152046 Hom.: 6585 Cov.: 33 AF XY: 0.269 AC XY: 19973 AN XY: 74312

African (AFR) AF: 0.137 AC: 5687 AN: 41498

American (AMR) AF: 0.202 AC: 3080 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.289 AC: 1003 AN: 3468

East Asian (EAS) AF: 0.0358 AC: 185 AN: 5172

South Asian (SAS) AF: 0.296 AC: 1430 AN: 4826

European-Finnish (FIN) AF: 0.367 AC: 3867 AN: 10542

Middle Eastern (MID) AF: 0.243 AC: 71 AN: 292

European-Non Finnish (NFE) AF: 0.366 AC: 24851 AN: 67960

Other (OTH) AF: 0.260 AC: 548 AN: 2104

Alfa AF: 0.302 Hom.: 4554

Bravo AF: 0.252

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Congenital contractures of the limbs and face, hypotonia, and developmental delay (1)
-	-	1	Hypotonia, infantile, with psychomotor retardation and characteristic facies 1 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.082
DANN	Benign	0.76
PhyloP100		-1.5
Mutation Taster		=99/1	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: rs3916906; hg19: chr13-101881777; COSMIC: COSV51924498;