rs17677552

Positions:

• chr13-101082860-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_052867.4(NALCN):​c.3714C>T​(p.Thr1238=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.352 in 1,613,572 control chromosomes in the GnomAD database, including 103,286 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7708 hom., cov: 32)
  • Exomes 𝑓: 0.36 (95578 hom.)
• Consequence: NALCN NM_052867.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.37

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 13-101082860-G-A is Benign according to our data. Variant chr13-101082860-G-A is described in ClinVar as [Benign]. Clinvar id is 262261.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-101082860-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.37 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.453 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NALCN	NM_052867.4	c.3714C>T	p.Thr1238=	synonymous_variant	33/44	ENST00000251127.11	NP_443099.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NALCN	ENST00000251127.11	c.3714C>T	p.Thr1238=	synonymous_variant	33/44	1	NM_052867.4	ENSP00000251127	P1

Frequencies

GnomAD3 genomes AF: 0.298 AC: 45203 AN: 151912 Hom.: 7698 Cov.: 32

Gnomad AFR AF: 0.129

Gnomad AMI AF: 0.396

Gnomad AMR AF: 0.266

Gnomad ASJ AF: 0.381

Gnomad EAS AF: 0.468

Gnomad SAS AF: 0.421

Gnomad FIN AF: 0.450

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.356

Gnomad OTH AF: 0.318

GnomAD3 exomes AF: 0.351 AC: 88076 AN: 251024 Hom.: 16408 AF XY: 0.361 AC XY: 48974 AN XY: 135682

Gnomad AFR exome AF: 0.128

Gnomad AMR exome AF: 0.239

Gnomad ASJ exome AF: 0.373

Gnomad EAS exome AF: 0.478

Gnomad SAS exome AF: 0.427

Gnomad FIN exome AF: 0.430

Gnomad NFE exome AF: 0.358

Gnomad OTH exome AF: 0.357

GnomAD4 exome AF: 0.357 AC: 522395 AN: 1461544 Hom.: 95578 Cov.: 45 AF XY: 0.361 AC XY: 262374 AN XY: 727106

Gnomad4 AFR exome AF: 0.125

Gnomad4 AMR exome AF: 0.244

Gnomad4 ASJ exome AF: 0.382

Gnomad4 EAS exome AF: 0.428

Gnomad4 SAS exome AF: 0.429

Gnomad4 FIN exome AF: 0.425

Gnomad4 NFE exome AF: 0.357

Gnomad4 OTH exome AF: 0.356

GnomAD4 genome AF: 0.297 AC: 45228 AN: 152028 Hom.: 7708 Cov.: 32 AF XY: 0.308 AC XY: 22855 AN XY: 74290

Gnomad4 AFR AF: 0.129

Gnomad4 AMR AF: 0.266

Gnomad4 ASJ AF: 0.381

Gnomad4 EAS AF: 0.468

Gnomad4 SAS AF: 0.422

Gnomad4 FIN AF: 0.450

Gnomad4 NFE AF: 0.355

Gnomad4 OTH AF: 0.320

Alfa AF: 0.344 Hom.: 18097

Bravo AF: 0.277

Asia WGS AF: 0.400 AC: 1393 AN: 3478

EpiCase AF: 0.359

EpiControl AF: 0.364

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 03, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Hypotonia, infantile, with psychomotor retardation and characteristic facies 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Congenital contractures of the limbs and face, hypotonia, and developmental delay Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.77
DANN	Benign	0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs17677552; hg19: chr13-101735211; COSMIC: COSV51918698;