rs786203988

Variant names:

• chr13-101191948-T-C
• rs786203988
• NM_052867.4:c.1733A>G

Your query was ambiguous. Multiple possible variants found:

• chr13-101191948-T-C
• chr13-101191948-T-G

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The ENST00000251127.11(NALCN):​c.1733A>G​(p.Tyr578Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y578S) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NALCN ENST00000251127.11 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 7.52
• Publications: 4 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: Pathogenic. The variant received 19 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in ENST00000251127.11
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-101191948-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 187775.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the NALCN gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 63 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Gene score misZ: 4.9555 (above the threshold of 3.09). Trascript score misZ: 6.7536 (above the threshold of 3.09). GenCC associations: The gene is linked to congenital contractures of the limbs and face, hypotonia, and developmental delay, temporal lobe epilepsy, hypotonia, infantile, with psychomotor retardation and characteristic facies 1, Sheldon-hall syndrome, digitotalar dysmorphism, hypotonia, infantile, with psychomotor retardation and characteristic facies, Freeman-Sheldon syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.94
• PP5: Variant 13-101191948-T-C is Pathogenic according to our data. Variant chr13-101191948-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 254646.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000251127.11. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NALCN	NM_052867.4	MANE Select	c.1733A>G	p.Tyr578Cys	missense	Exon 14 of 44	NP_443099.1
	NALCN	NM_001350748.2		c.1733A>G	p.Tyr578Cys	missense	Exon 14 of 45	NP_001337677.1
	NALCN	NM_001350749.2		c.1733A>G	p.Tyr578Cys	missense	Exon 14 of 44	NP_001337678.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NALCN	ENST00000251127.11	TSL:1 MANE Select	c.1733A>G	p.Tyr578Cys	missense	Exon 14 of 44	ENSP00000251127.6
	NALCN	ENST00000470333.1	TSL:1	n.1829A>G		non_coding_transcript_exon	Exon 14 of 15
	NALCN	ENST00000675332.1		c.1733A>G	p.Tyr578Cys	missense	Exon 14 of 45	ENSP00000501955.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Congenital contractures of the limbs and face, hypotonia, and developmental delay (3)
2	-	-	not provided (2)
1	-	-	Arthrogryposis syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		7.5
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-8.0	D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.62		Gain of catalytic residue at V575 (P = 0)
MVP		0.80
MPC		2.2
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.96
gMVP		0.99
Mutation Taster		=1/99	disease causing (ClinVar)

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: rs786203988; hg19: chr13-101844299;