13-101068677-T-C

Variant names:

• chr13-101068677-T-C
• rs11616341
• NM_052867.4:c.4330+18A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_052867.4(NALCN):​c.4330+18A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.263 in 1,563,004 control chromosomes in the GnomAD database, including 57,151 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6417 hom., cov: 32)
  • Exomes 𝑓: 0.26 (50734 hom.)
• Consequence: NALCN NM_052867.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.902
• Publications: 9 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 13-101068677-T-C is Benign according to our data. Variant chr13-101068677-T-C is described in ClinVar as Benign. ClinVar VariationId is 262262.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.353 is higher than 0.05.

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.4330+18A>G		intron	N/A	NP_443099.1
	NALCN	NM_001350748.2		c.4417+18A>G		intron	N/A	NP_001337677.1
	NALCN	NM_001350749.2		c.4330+18A>G		intron	N/A	NP_001337678.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NALCN	ENST00000251127.11	TSL:1 MANE Select	c.4330+18A>G		intron	N/A	ENSP00000251127.6
	NALCN	ENST00000675332.1		c.4417+18A>G		intron	N/A	ENSP00000501955.1
	NALCN	ENST00000858715.1		c.4330+18A>G		intron	N/A	ENSP00000528774.1

Frequencies

GnomAD3 genomes AF: 0.278 AC: 42302 AN: 151898 Hom.: 6416 Cov.: 32

Gnomad AFR AF: 0.359

Gnomad AMI AF: 0.320

Gnomad AMR AF: 0.197

Gnomad ASJ AF: 0.301

Gnomad EAS AF: 0.00616

Gnomad SAS AF: 0.178

Gnomad FIN AF: 0.247

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.280

Gnomad OTH AF: 0.271

GnomAD2 exomes AF: 0.231 AC: 50604 AN: 219412 AF XY: 0.230

Gnomad AFR exome AF: 0.356

Gnomad AMR exome AF: 0.130

Gnomad ASJ exome AF: 0.300

Gnomad EAS exome AF: 0.00437

Gnomad FIN exome AF: 0.245

Gnomad NFE exome AF: 0.278

Gnomad OTH exome AF: 0.238

GnomAD4 exome AF: 0.261 AC: 367970 AN: 1410988 Hom.: 50734 Cov.: 31 AF XY: 0.258 AC XY: 180588 AN XY: 698722

African (AFR) AF: 0.358 AC: 11245 AN: 31392

American (AMR) AF: 0.138 AC: 5201 AN: 37596

Ashkenazi Jewish (ASJ) AF: 0.298 AC: 7329 AN: 24582

East Asian (EAS) AF: 0.00283 AC: 107 AN: 37748

South Asian (SAS) AF: 0.172 AC: 13084 AN: 75954

European-Finnish (FIN) AF: 0.247 AC: 12970 AN: 52468

Middle Eastern (MID) AF: 0.236 AC: 1318 AN: 5580

European-Non Finnish (NFE) AF: 0.278 AC: 301935 AN: 1087434

Other (OTH) AF: 0.254 AC: 14781 AN: 58234

GnomAD4 genome AF: 0.278 AC: 42325 AN: 152016 Hom.: 6417 Cov.: 32 AF XY: 0.270 AC XY: 20032 AN XY: 74314

African (AFR) AF: 0.358 AC: 14845 AN: 41434

American (AMR) AF: 0.196 AC: 2999 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.301 AC: 1043 AN: 3466

East Asian (EAS) AF: 0.00618 AC: 32 AN: 5180

South Asian (SAS) AF: 0.177 AC: 852 AN: 4824

European-Finnish (FIN) AF: 0.247 AC: 2613 AN: 10560

Middle Eastern (MID) AF: 0.207 AC: 61 AN: 294

European-Non Finnish (NFE) AF: 0.280 AC: 19016 AN: 67954

Other (OTH) AF: 0.272 AC: 573 AN: 2108

Alfa AF: 0.275 Hom.: 14673

Bravo AF: 0.278

Asia WGS AF: 0.138 AC: 481 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.8
DANN	Benign	0.60
PhyloP100		0.90
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs11616341; hg19: chr13-101721029;