chr9-135786336-G-C

Variant names:

• chr9-135786336-G-C
• rs561255614
• NM_020822.3:c.3317G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_020822.3(KCNT1):​c.3317G>C​(p.Arg1106Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000694 in 1,441,676 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1106W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: KCNT1 NM_020822.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.18
• Publications: 8 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: Likely_benign. The variant received -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.895
• BS2: High AC in GnomAdExome4 at 10 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020822.3. 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
	KCNT1	NM_020822.3	MANE Select	c.3317G>C	p.Arg1106Pro	missense	Exon 29 of 31	NP_065873.2
	KCNT1	NM_001272003.2		c.3182G>C	p.Arg1061Pro	missense	Exon 28 of 31	NP_001258932.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNT1	ENST00000371757.7	TSL:1 MANE Select	c.3317G>C	p.Arg1106Pro	missense	Exon 29 of 31	ENSP00000360822.2
	KCNT1	ENST00000460750.5	TSL:1	n.*2927G>C		non_coding_transcript_exon	Exon 29 of 32	ENSP00000418777.1
	KCNT1	ENST00000460750.5	TSL:1	n.*2927G>C		3_prime_UTR	Exon 29 of 32	ENSP00000418777.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000503 AC: 1 AN: 198616 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000119

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000694 AC: 10 AN: 1441676 Hom.: 0 Cov.: 36 AF XY: 0.00000419 AC XY: 3 AN XY: 715244

African (AFR) AF: 0.00 AC: 0 AN: 33172

American (AMR) AF: 0.00 AC: 0 AN: 41444

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25602

East Asian (EAS) AF: 0.00 AC: 0 AN: 38922

South Asian (SAS) AF: 0.00 AC: 0 AN: 83948

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50152

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5218

European-Non Finnish (NFE) AF: 0.00000906 AC: 10 AN: 1103660

Other (OTH) AF: 0.00 AC: 0 AN: 59558

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000175 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jan 17, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A variant of uncertain significance has been identified in the KCNT1 gene. The R1106P variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R106P variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R1106P variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, a different missense variant at the same codon (R1106Q) have been reported in Human Gene Mutation Database in association with KCNT1-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Benign	-0.45	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		9.2
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.41
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Vest4		0.91
MVP		0.58
MPC		0.55
ClinPred		0.98	D
GERP RS		4.8
Varity_R		0.77
gMVP		0.63
Mutation Taster		=0/100	disease causing

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: rs561255614; hg19: chr9-138678182;