rs78817184

Variant names:

• chr13-101057985-G-A
• rs78817184
• NM_052867.4:c.4977C>T
• NALCN p.Asp1659Asp

Your query was ambiguous. Multiple possible variants found:

• chr13-101057985-G-A
• chr13-101057985-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_052867.4(NALCN):​c.4977C>T​(p.Asp1659Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0033 in 1,613,936 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (22 hom.)
• Consequence: NALCN NM_052867.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0910
• 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-AS1 (HGNC:42743): (NALCN antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 13-101057985-G-A is Benign according to our data. Variant chr13-101057985-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262264.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.091 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00302 (460/152290) while in subpopulation NFE AF = 0.00497 (338/68026). AF 95% confidence interval is 0.00453. There are 2 homozygotes in GnomAd4. There are 193 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_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.4977C>T	p.Asp1659Asp	synonymous	Exon 43 of 44	NP_443099.1	Q8IZF0-1
	NALCN	NM_001350748.2		c.5064C>T	p.Asp1688Asp	synonymous	Exon 44 of 45	NP_001337677.1	A0A6Q8PFS9
	NALCN	NM_001350749.2		c.4977C>T	p.Asp1659Asp	synonymous	Exon 43 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.4977C>T	p.Asp1659Asp	synonymous	Exon 43 of 44	ENSP00000251127.6	Q8IZF0-1
	NALCN	ENST00000675332.1		c.5064C>T	p.Asp1688Asp	synonymous	Exon 44 of 45	ENSP00000501955.1	A0A6Q8PFS9
	NALCN	ENST00000858715.1		c.4977C>T	p.Asp1659Asp	synonymous	Exon 43 of 44	ENSP00000528774.1

Frequencies

GnomAD3 genomes AF: 0.00302 AC: 459 AN: 152172 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000628

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00678

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00497

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00302 AC: 758 AN: 250996 AF XY: 0.00312

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00497

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00732

Gnomad NFE exome AF: 0.00445

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.00333 AC: 4869 AN: 1461646 Hom.: 22 Cov.: 30 AF XY: 0.00343 AC XY: 2492 AN XY: 727166

African (AFR) AF: 0.000926 AC: 31 AN: 33480

American (AMR) AF: 0.000425 AC: 19 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00409 AC: 107 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86258

European-Finnish (FIN) AF: 0.00761 AC: 405 AN: 53188

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00369 AC: 4107 AN: 1112000

Other (OTH) AF: 0.00308 AC: 186 AN: 60394

GnomAD4 genome AF: 0.00302 AC: 460 AN: 152290 Hom.: 2 Cov.: 32 AF XY: 0.00259 AC XY: 193 AN XY: 74468

African (AFR) AF: 0.000650 AC: 27 AN: 41544

American (AMR) AF: 0.000523 AC: 8 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00374 AC: 13 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00678 AC: 72 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00497 AC: 338 AN: 68026

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.0192 Hom.: 1969

Bravo AF: 0.00221

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00294

EpiControl AF: 0.00320

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	NALCN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.051
DANN	Benign	0.75
PhyloP100		-0.091
Mutation Taster		=100/0	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs78817184;

hg19: chr13-101710337;

COSMIC: COSV51921215;