chr13-101067948-T-G

Variant names:

• chr13-101067948-T-G
• rs1289556
• NM_052867.4:c.4416A>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001350748.2(NALCN):​c.4503A>C​(p.Ile1501Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.364 in 1,610,586 control chromosomes in the GnomAD database, including 114,351 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (17334 hom., cov: 33)
  • Exomes 𝑓: 0.36 (97017 hom.)
• Consequence: NALCN NM_001350748.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.08
• Publications: 20 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 13-101067948-T-G is Benign according to our data. Variant chr13-101067948-T-G is described in ClinVar as Benign. ClinVar VariationId is 262263.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.08 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.708 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001350748.2. 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.4416A>C	p.Ile1472Ile	synonymous	Exon 39 of 44	NP_443099.1
	NALCN	NM_001350748.2		c.4503A>C	p.Ile1501Ile	synonymous	Exon 40 of 45	NP_001337677.1
	NALCN	NM_001350749.2		c.4416A>C	p.Ile1472Ile	synonymous	Exon 39 of 44	NP_001337678.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NALCN	ENST00000251127.11	TSL:1 MANE Select	c.4416A>C	p.Ile1472Ile	synonymous	Exon 39 of 44	ENSP00000251127.6
	NALCN	ENST00000675332.1		c.4503A>C	p.Ile1501Ile	synonymous	Exon 40 of 45	ENSP00000501955.1
	NALCN	ENST00000858715.1		c.4416A>C	p.Ile1472Ile	synonymous	Exon 39 of 44	ENSP00000528774.1

Frequencies

GnomAD3 genomes AF: 0.443 AC: 67239 AN: 151916 Hom.: 17302 Cov.: 33

Gnomad AFR AF: 0.715

Gnomad AMI AF: 0.360

Gnomad AMR AF: 0.291

Gnomad ASJ AF: 0.426

Gnomad EAS AF: 0.134

Gnomad SAS AF: 0.340

Gnomad FIN AF: 0.350

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.360

Gnomad OTH AF: 0.407

GnomAD2 exomes AF: 0.341 AC: 85333 AN: 250328 AF XY: 0.340

Gnomad AFR exome AF: 0.719

Gnomad AMR exome AF: 0.185

Gnomad ASJ exome AF: 0.424

Gnomad EAS exome AF: 0.125

Gnomad FIN exome AF: 0.354

Gnomad NFE exome AF: 0.360

Gnomad OTH exome AF: 0.342

GnomAD4 exome AF: 0.356 AC: 518861 AN: 1458552 Hom.: 97017 Cov.: 32 AF XY: 0.355 AC XY: 257469 AN XY: 725648

African (AFR) AF: 0.728 AC: 24302 AN: 33396

American (AMR) AF: 0.195 AC: 8678 AN: 44540

Ashkenazi Jewish (ASJ) AF: 0.422 AC: 11011 AN: 26088

East Asian (EAS) AF: 0.151 AC: 5984 AN: 39662

South Asian (SAS) AF: 0.333 AC: 28546 AN: 85842

European-Finnish (FIN) AF: 0.358 AC: 19129 AN: 53394

Middle Eastern (MID) AF: 0.368 AC: 2120 AN: 5762

European-Non Finnish (NFE) AF: 0.358 AC: 396940 AN: 1109548

Other (OTH) AF: 0.367 AC: 22151 AN: 60320

GnomAD4 genome AF: 0.443 AC: 67305 AN: 152034 Hom.: 17334 Cov.: 33 AF XY: 0.433 AC XY: 32215 AN XY: 74318

African (AFR) AF: 0.714 AC: 29610 AN: 41450

American (AMR) AF: 0.290 AC: 4437 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.426 AC: 1477 AN: 3464

East Asian (EAS) AF: 0.134 AC: 691 AN: 5170

South Asian (SAS) AF: 0.337 AC: 1626 AN: 4818

European-Finnish (FIN) AF: 0.350 AC: 3701 AN: 10574

Middle Eastern (MID) AF: 0.354 AC: 104 AN: 294

European-Non Finnish (NFE) AF: 0.360 AC: 24469 AN: 67962

Other (OTH) AF: 0.408 AC: 862 AN: 2112

Alfa AF: 0.384 Hom.: 24480

Bravo AF: 0.446

Asia WGS AF: 0.292 AC: 1013 AN: 3478

EpiCase AF: 0.360

EpiControl AF: 0.357

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	7.1
DANN	Benign	0.80
PhyloP100		2.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs1289556; hg19: chr13-101720300; COSMIC: COSV51933813;