13-101057985-G-C

Position:

• chr13-101057985-G-C

Variant summary

Our verdict is Benign. Variant got -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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. D1659D) has been classified as Likely benign.

• 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:3
• Conservation: PhyloP100: -0.0910

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 Benign. Variant got -8 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NALCN. . Gene score misZ 4.9555 (greater than the threshold 3.09). Trascript score misZ 6.7536 (greater than threshold 3.09). GenCC has associacion of gene with 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=0.005455643).
• 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 id is 502132.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NALCN	NM_052867.4	c.4977C>G	p.Asp1659Glu	missense_variant	43/44	ENST00000251127.11	NP_443099.1
NALCN-AS1	NR_047687.1	n.1545G>C		non_coding_transcript_exon_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NALCN	ENST00000251127.11	c.4977C>G	p.Asp1659Glu	missense_variant	43/44	1	NM_052867.4	ENSP00000251127	P1
NALCN-AS1	ENST00000457843.1	n.1545G>C		non_coding_transcript_exon_variant	8/8	2

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

GnomAD3 exomes AF: 0.000426 AC: 107 AN: 250996 Hom.: 0 AF XY: 0.000324 AC XY: 44 AN XY: 135694

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 SAS 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

Gnomad4 AFR exome AF: 0.00496

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000495

Gnomad4 OTH exome AF: 0.000381

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

Gnomad4 AFR AF: 0.00530

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00000940 Hom.: 1968

Bravo AF: 0.00173

ExAC AF: 0.000519 AC: 63

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 30, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 27, 2021	- -

NALCN-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 15, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	0.93	N
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

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