NM_020822.3:c.1700G>T

Variant names:

• chr9-135770378-G-T
• rs781375160
• NM_020822.3:c.1700G>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_020822.3(KCNT1):​c.1700G>T​(p.Gly567Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,460,954 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: KCNT1 NM_020822.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.88
• Publications: 0 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: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.22177789).
• BP6: Variant 9-135770378-G-T is Benign according to our data. Variant chr9-135770378-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 540573.
• BS2: High AC in GnomAdExome4 at 7 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNT1	NM_020822.3	MANE Select	c.1700G>T	p.Gly567Val	missense	Exon 17 of 31	NP_065873.2
	KCNT1	NM_001272003.2		c.1565G>T	p.Gly522Val	missense	Exon 16 of 31	NP_001258932.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNT1	ENST00000371757.7	TSL:1 MANE Select	c.1700G>T	p.Gly567Val	missense	Exon 17 of 31	ENSP00000360822.2
	KCNT1	ENST00000460750.5	TSL:1	n.*1310G>T		non_coding_transcript_exon	Exon 17 of 32	ENSP00000418777.1
	KCNT1	ENST00000460750.5	TSL:1	n.*1310G>T		3_prime_UTR	Exon 17 of 32	ENSP00000418777.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000798 AC: 2 AN: 250658 AF XY: 0.0000147

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1460954 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 726836

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26088

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52864

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111790

Other (OTH) AF: 0.0000166 AC: 1 AN: 60356

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Developmental and epileptic encephalopathy, 14;C3554306:Autosomal dominant nocturnal frontal lobe epilepsy 5 (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.9
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-4.2	D
REVEL	Benign	0.079
Sift	Benign	0.031	D
Sift4G	Benign	0.070	T
Polyphen		0.0060	B
Vest4		0.47
MutPred		0.53		Loss of catalytic residue at G548 (P = 0.0233)
MVP		0.48
MPC		0.81
ClinPred		0.50	T
GERP RS		1.5
Varity_R		0.33
gMVP		0.80
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs781375160; hg19: chr9-138662224;