NM_052867.4:c.4977C>G

Variant names:

• chr13-101057985-G-C
• rs78817184
• NM_052867.4:c.4977C>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS1

The NM_052867.4(NALCN):​c.4977C>G​(p.Asp1659Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0003 in 1,613,936 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1659A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0015 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: NALCN NM_052867.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• 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 -8 ACMG points.

• PP2: Missense variant in the NALCN gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 63 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Gene score misZ: 4.9555 (above the threshold of 3.09). Trascript score misZ: 6.7536 (above the threshold of 3.09). GenCC associations: The gene is linked to congenital contractures of the limbs and face, hypotonia, and developmental delay, temporal lobe epilepsy, hypotonia, infantile, with psychomotor retardation and characteristic facies 1, Sheldon-hall syndrome, digitotalar dysmorphism, hypotonia, infantile, with psychomotor retardation and characteristic facies, Freeman-Sheldon syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.005455643).
• BP6: Variant 13-101057985-G-C is Benign according to our data. Variant chr13-101057985-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 502132.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00148 (225/152290) while in subpopulation AFR AF = 0.0053 (220/41544). AF 95% confidence interval is 0.00472. There are 1 homozygotes in GnomAd4. There are 106 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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>G	p.Asp1659Glu	missense	Exon 43 of 44	NP_443099.1	Q8IZF0-1
	NALCN	NM_001350748.2		c.5064C>G	p.Asp1688Glu	missense	Exon 44 of 45	NP_001337677.1	A0A6Q8PFS9
	NALCN	NM_001350749.2		c.4977C>G	p.Asp1659Glu	missense	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>G	p.Asp1659Glu	missense	Exon 43 of 44	ENSP00000251127.6	Q8IZF0-1
	NALCN	ENST00000675332.1		c.5064C>G	p.Asp1688Glu	missense	Exon 44 of 45	ENSP00000501955.1	A0A6Q8PFS9
	NALCN	ENST00000858715.1		c.4977C>G	p.Asp1659Glu	missense	Exon 43 of 44	ENSP00000528774.1

Frequencies

GnomAD3 genomes AF: 0.00148 AC: 225 AN: 152172 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000426 AC: 107 AN: 250996 AF XY: 0.000324

Gnomad AFR exome AF: 0.00566

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000177 AC: 259 AN: 1461646 Hom.: 0 Cov.: 30 AF XY: 0.000153 AC XY: 111 AN XY: 727166

African (AFR) AF: 0.00496 AC: 166 AN: 33480

American (AMR) AF: 0.000313 AC: 14 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53188

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000495 AC: 55 AN: 1112000

Other (OTH) AF: 0.000381 AC: 23 AN: 60394

GnomAD4 genome AF: 0.00148 AC: 225 AN: 152290 Hom.: 1 Cov.: 32 AF XY: 0.00142 AC XY: 106 AN XY: 74468

African (AFR) AF: 0.00530 AC: 220 AN: 41544

American (AMR) AF: 0.000261 AC: 4 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00000757 Hom.: 1969

Bravo AF: 0.00173

ExAC AF: 0.000519 AC: 63

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	1	Inborn genetic diseases (1)
-	-	1	NALCN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	0.0080
DANN	Benign	0.63
DEOGEN2	Benign	0.14	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.077	N
LIST_S2	Benign	0.76	T
M_CAP	Uncertain	0.091	D
MetaRNN	Benign	0.0055	T
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	0.55	N
PhyloP100		-0.091
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.28
Sift	Benign	0.63	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.17
MutPred		0.28		Gain of helix (P = 0.0082)
MVP		0.25
MPC		0.41
ClinPred		0.0095	T
GERP RS		-10
Varity_R		0.032
gMVP		0.52
Mutation Taster		=79/21	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

Other links and lift over

dbSNP: rs78817184; hg19: chr13-101710337; COSMIC: COSV51950687;