chr13-101111178-G-A

Variant names:

• chr13-101111178-G-A
• rs79264337
• NM_052867.4:c.2241C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_052867.4(NALCN):​c.2241C>T​(p.Pro747Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00371 in 1,608,526 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0049 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0036 (10 hom.)
• Consequence: NALCN NM_052867.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -4.83
• Publications: 1 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 Gene-Disease associations (from GenCC):

• congenital contractures of the limbs and face, hypotonia, and developmental delay

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• hypotonia, infantile, with psychomotor retardation and characteristic facies 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• digitotalar dysmorphism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Freeman-Sheldon syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Sheldon-hall syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hypotonia, infantile, with psychomotor retardation and characteristic facies

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• temporal lobe epilepsy

  Inheritance: AD Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 13-101111178-G-A is Benign according to our data. Variant chr13-101111178-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.83 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00494 (751/152164) while in subpopulation AFR AF = 0.0104 (430/41518). AF 95% confidence interval is 0.00955. There are 2 homozygotes in GnomAd4. There are 340 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

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.2241C>T	p.Pro747Pro	synonymous	Exon 19 of 44	NP_443099.1	Q8IZF0-1
	NALCN	NM_001350748.2		c.2328C>T	p.Pro776Pro	synonymous	Exon 20 of 45	NP_001337677.1	A0A6Q8PFS9
	NALCN	NM_001350749.2		c.2241C>T	p.Pro747Pro	synonymous	Exon 19 of 44	NP_001337678.1	Q8IZF0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NALCN	ENST00000251127.11	TSL:1 MANE Select	c.2241C>T	p.Pro747Pro	synonymous	Exon 19 of 44	ENSP00000251127.6	Q8IZF0-1
	NALCN	ENST00000675332.1		c.2328C>T	p.Pro776Pro	synonymous	Exon 20 of 45	ENSP00000501955.1	A0A6Q8PFS9
	NALCN	ENST00000858715.1		c.2241C>T	p.Pro747Pro	synonymous	Exon 19 of 44	ENSP00000528774.1

Frequencies

GnomAD3 genomes AF: 0.00493 AC: 750 AN: 152046 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00256

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00382

Gnomad OTH AF: 0.00336

GnomAD2 exomes AF: 0.00277 AC: 693 AN: 250570 AF XY: 0.00272

Gnomad AFR exome AF: 0.00954

Gnomad AMR exome AF: 0.00194

Gnomad ASJ exome AF: 0.000795

Gnomad EAS exome AF: 0.000272

Gnomad FIN exome AF: 0.000754

Gnomad NFE exome AF: 0.00362

Gnomad OTH exome AF: 0.00376

GnomAD4 exome AF: 0.00359 AC: 5223 AN: 1456362 Hom.: 10 Cov.: 31 AF XY: 0.00340 AC XY: 2463 AN XY: 723538

African (AFR) AF: 0.00984 AC: 329 AN: 33418

American (AMR) AF: 0.00213 AC: 95 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.000690 AC: 18 AN: 26088

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39530

South Asian (SAS) AF: 0.000372 AC: 32 AN: 85970

European-Finnish (FIN) AF: 0.000871 AC: 46 AN: 52788

Middle Eastern (MID) AF: 0.00347 AC: 20 AN: 5760

European-Non Finnish (NFE) AF: 0.00398 AC: 4407 AN: 1108012

Other (OTH) AF: 0.00452 AC: 272 AN: 60124

GnomAD4 genome AF: 0.00494 AC: 751 AN: 152164 Hom.: 2 Cov.: 32 AF XY: 0.00457 AC XY: 340 AN XY: 74384

African (AFR) AF: 0.0104 AC: 430 AN: 41518

American (AMR) AF: 0.00255 AC: 39 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10580

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00382 AC: 260 AN: 68024

Other (OTH) AF: 0.00332 AC: 7 AN: 2108

Alfa AF: 0.00369 Hom.: 1

Bravo AF: 0.00532

Asia WGS AF: 0.00144 AC: 5 AN: 3476

EpiCase AF: 0.00404

EpiControl AF: 0.00350

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	1	Hypotonia, infantile, with psychomotor retardation and characteristic facies 1;C4225398:Congenital contractures of the limbs and face, hypotonia, and developmental delay (1)
-	-	1	NALCN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.11
DANN	Benign	0.80
PhyloP100		-4.8
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs79264337; hg19: chr13-101763529; COSMIC: COSV51959387;