13-101104660-A-C

Position:

• chr13-101104660-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_052867.4(NALCN):​c.2637-10T>G variant causes a splice polypyrimidine tract, intron change. The variant allele was found at a frequency of 0.025 in 1,613,486 control chromosomes in the GnomAD database, including 680 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (73 hom., cov: 33)
  • Exomes 𝑓: 0.025 (607 hom.)
• Consequence: NALCN NM_052867.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.8343
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 4.23

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 13-101104660-A-C is Benign according to our data. Variant chr13-101104660-A-C is described in ClinVar as [Benign]. Clinvar id is 262258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-101104660-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0634 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NALCN	NM_052867.4	c.2637-10T>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000251127.11	NP_443099.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NALCN	ENST00000251127.11	c.2637-10T>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_052867.4	ENSP00000251127	P1

Frequencies

GnomAD3 genomes AF: 0.0265 AC: 4036 AN: 152140 Hom.: 70 Cov.: 33

Gnomad AFR AF: 0.0360

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.0175

Gnomad ASJ AF: 0.0274

Gnomad EAS AF: 0.0694

Gnomad SAS AF: 0.0456

Gnomad FIN AF: 0.00311

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0217

Gnomad OTH AF: 0.0263

GnomAD3 exomes AF: 0.0268 AC: 6703 AN: 250344 Hom.: 124 AF XY: 0.0278 AC XY: 3765 AN XY: 135258

Gnomad AFR exome AF: 0.0360

Gnomad AMR exome AF: 0.0134

Gnomad ASJ exome AF: 0.0277

Gnomad EAS exome AF: 0.0701

Gnomad SAS exome AF: 0.0458

Gnomad FIN exome AF: 0.00421

Gnomad NFE exome AF: 0.0217

Gnomad OTH exome AF: 0.0261

GnomAD4 exome AF: 0.0248 AC: 36218 AN: 1461228 Hom.: 607 Cov.: 31 AF XY: 0.0252 AC XY: 18305 AN XY: 726898

Gnomad4 AFR exome AF: 0.0357

Gnomad4 AMR exome AF: 0.0140

Gnomad4 ASJ exome AF: 0.0276

Gnomad4 EAS exome AF: 0.0827

Gnomad4 SAS exome AF: 0.0436

Gnomad4 FIN exome AF: 0.00444

Gnomad4 NFE exome AF: 0.0222

Gnomad4 OTH exome AF: 0.0266

GnomAD4 genome AF: 0.0266 AC: 4051 AN: 152258 Hom.: 73 Cov.: 33 AF XY: 0.0258 AC XY: 1919 AN XY: 74456

Gnomad4 AFR AF: 0.0361

Gnomad4 AMR AF: 0.0175

Gnomad4 ASJ AF: 0.0274

Gnomad4 EAS AF: 0.0694

Gnomad4 SAS AF: 0.0465

Gnomad4 FIN AF: 0.00311

Gnomad4 NFE AF: 0.0217

Gnomad4 OTH AF: 0.0279

Alfa AF: 0.0245 Hom.: 35

Bravo AF: 0.0270

Asia WGS AF: 0.0680 AC: 238 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

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

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

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

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	14
DANN	Benign	0.78

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.83
dbscSNV1_RF	Benign	0.68
SpliceAI score (max)		0.39		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.39		Position offset: -10

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs16958350; hg19: chr13-101757011; COSMIC: COSV51954690;