9-135778781-G-C

Variant names:

• chr9-135778781-G-C
• rs797044544
• NM_020822.3:c.2688G>C

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PS1 PM2 PM5 PP3 PP5_Moderate

The NM_020822.3(KCNT1):​c.2688G>C​(p.Met896Ile) 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 Pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M896K) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNT1 NM_020822.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.65
• Publications: 11 publications found

Genes affected

KCNT1 (HGNC:18865): (potassium sodium-activated channel subfamily T member 1) Potassium channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. This gene encodes a sodium-activated potassium channel subunit which is thought to function in ion conductance and developmental signaling pathways. Mutations in this gene cause the early-onset epileptic disorders, malignant migrating partial seizures of infancy and autosomal dominant nocturnal frontal lobe epilepsy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2012]

KCNT1 Gene-Disease associations (from GenCC):

• childhood-onset epilepsy syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• developmental and epileptic encephalopathy, 14

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• malignant migrating partial seizures of infancy

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• autosomal dominant nocturnal frontal lobe epilepsy 5

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• autosomal dominant nocturnal frontal lobe epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PS1: Transcript NM_020822.3 (KCNT1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 183028
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-135778780-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 1457517.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.824
• PP5: Variant 9-135778781-G-C is Pathogenic according to our data. Variant chr9-135778781-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 379933.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNT1	NM_020822.3	c.2688G>C	p.Met896Ile	missense_variant	Exon 23 of 31	ENST00000371757.7	NP_065873.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNT1	ENST00000371757.7	c.2688G>C	p.Met896Ile	missense_variant	Exon 23 of 31	1	NM_020822.3	ENSP00000360822.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Jun 10, 2015

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2688 G>C (M896I) variant in the KCNT1 gene has not been reported previously as a pathogenic variant nor as a benign polymorphism, to our knowledge. The c.2688 G>C (M896I) variant wasnot observed in approximately 6500 individuals of European and African American ancestry in the NHLBIExome Sequencing Project, indicating it is not a common benign variant in these populations. The M896Isubstitution is a conservative amino acid substitution, which is not likely to impact secondary protein structureas these residues share similar properties. However, this substitution occurs at a position that is conservedacross species and in silico analysis predicts this variant is probably damaging to the proteinstructure/function. In addition, a different nucleotide change at the same residue (c.2688 G>A; p.M896I)has been reported as a de novo change in an individual with nocturnal frontal lobe epilepsy and psychiatricproblems (Heron et al., 2012), supporting the functional importance of this region of the protein. Weinterpret M896I as a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	.;.;.;.;.;.;.;.;T;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.072	D
MutationAssessor	Uncertain	2.6	.;.;.;.;.;.;.;.;M;.
PhyloP100		9.7
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-2.3	.;.;N;.;.;.;.;.;N;N
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0090	.;.;D;.;.;.;.;.;D;D
Sift4G	Uncertain	0.012	D;D;D;D;D;D;D;D;D;D
Polyphen		0.76	.;.;.;.;.;.;.;.;P;.
Vest4		0.91
MutPred		0.38		.;.;.;.;.;.;Loss of disorder (P = 0.0815);Loss of disorder (P = 0.0815);Loss of disorder (P = 0.0815);.;
MVP		0.85
MPC		0.81
ClinPred		0.97	D
GERP RS		4.5
Varity_R		0.57
gMVP		0.96
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs797044544; hg19: chr9-138670627;