13-101055386-G-C

Variant names:

• chr13-101055386-G-C
• rs373221131
• NM_052867.4:c.5126C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_052867.4(NALCN):​c.5126C>G​(p.Ala1709Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NALCN NM_052867.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.21

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 hypotonia, infantile, with psychomotor retardation and characteristic facies 1, digitotalar dysmorphism, hypotonia, infantile, with psychomotor retardation and characteristic facies, congenital contractures of the limbs and face, hypotonia, and developmental delay, Freeman-Sheldon syndrome, Sheldon-hall syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.06935391).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NALCN	NM_052867.4	c.5126C>G	p.Ala1709Gly	missense_variant	Exon 44 of 44	ENST00000251127.11	NP_443099.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NALCN	ENST00000251127.11	c.5126C>G	p.Ala1709Gly	missense_variant	Exon 44 of 44	1	NM_052867.4	ENSP00000251127.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.42
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.069	T
MetaSVM	Uncertain	0.29	D
MutationAssessor	Benign	0.0	N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.54	N
REVEL	Benign	0.25
Sift	Benign	0.36	T
Sift4G	Benign	0.34	T
Polyphen		0.083	B
Vest4		0.056
MutPred		0.28		Gain of catalytic residue at D1708 (P = 0.0013);
MVP		0.40
MPC		0.45
ClinPred		0.21	T
GERP RS		4.6
Varity_R		0.047
gMVP		0.50

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

Publications

LitVar

Other links and lift over

dbSNP: rs373221131; hg19: chr13-101707738;