rs149804567

Variant names:

• chr9-135778444-A-G
• rs149804567
• NM_020822.3:c.2543A>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP3 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020822.3(KCNT1):​c.2543A>G​(p.Glu848Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00293 in 1,552,002 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0030 (9 hom.)
• Consequence: KCNT1 NM_020822.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 9.00
• Publications: 10 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 -19 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_noAF, Cadd, Dann, M_CAP, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.021965742).
• BP6: Variant 9-135778444-A-G is Benign according to our data. Variant chr9-135778444-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129358.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00231 (352/152290) while in subpopulation AMR AF = 0.00444 (68/15312). AF 95% confidence interval is 0.00359. There are 1 homozygotes in GnomAd4. There are 182 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 352 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.2543A>G	p.Glu848Gly	missense	Exon 22 of 31	NP_065873.2
	KCNT1	NM_001272003.2		c.2408A>G	p.Glu803Gly	missense	Exon 21 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.2543A>G	p.Glu848Gly	missense	Exon 22 of 31	ENSP00000360822.2
	KCNT1	ENST00000460750.5	TSL:1	n.*2153A>G		non_coding_transcript_exon	Exon 22 of 32	ENSP00000418777.1
	KCNT1	ENST00000460750.5	TSL:1	n.*2153A>G		3_prime_UTR	Exon 22 of 32	ENSP00000418777.1

Frequencies

GnomAD3 genomes AF: 0.00231 AC: 352 AN: 152172 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00445

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00103

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00346

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00229 AC: 361 AN: 157314 AF XY: 0.00226

Gnomad AFR exome AF: 0.000340

Gnomad AMR exome AF: 0.00391

Gnomad ASJ exome AF: 0.000352

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00145

Gnomad NFE exome AF: 0.00329

Gnomad OTH exome AF: 0.00405

GnomAD4 exome AF: 0.00300 AC: 4200 AN: 1399712 Hom.: 9 Cov.: 32 AF XY: 0.00287 AC XY: 1981 AN XY: 690470

African (AFR) AF: 0.000632 AC: 20 AN: 31628

American (AMR) AF: 0.00408 AC: 146 AN: 35760

Ashkenazi Jewish (ASJ) AF: 0.000159 AC: 4 AN: 25178

East Asian (EAS) AF: 0.00 AC: 0 AN: 35792

South Asian (SAS) AF: 0.000844 AC: 67 AN: 79366

European-Finnish (FIN) AF: 0.000798 AC: 39 AN: 48896

Middle Eastern (MID) AF: 0.00773 AC: 44 AN: 5690

European-Non Finnish (NFE) AF: 0.00343 AC: 3698 AN: 1079374

Other (OTH) AF: 0.00314 AC: 182 AN: 58028

GnomAD4 genome AF: 0.00231 AC: 352 AN: 152290 Hom.: 1 Cov.: 33 AF XY: 0.00244 AC XY: 182 AN XY: 74468

African (AFR) AF: 0.000553 AC: 23 AN: 41562

American (AMR) AF: 0.00444 AC: 68 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00103 AC: 5 AN: 4834

European-Finnish (FIN) AF: 0.00103 AC: 11 AN: 10628

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00346 AC: 235 AN: 68002

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00298 Hom.: 7

Bravo AF: 0.00235

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.000942 AC: 4

ESP6500EA AF: 0.00288 AC: 24

ExAC AF: 0.000843 AC: 86

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	4	not specified (4)
-	-	2	Developmental and epileptic encephalopathy, 14 (2)
-	-	1	Autosomal dominant nocturnal frontal lobe epilepsy 5 (1)
-	-	1	Developmental and epileptic encephalopathy, 14;C3554306:Autosomal dominant nocturnal frontal lobe epilepsy 5 (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.31	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.52	D
MetaRNN	Benign	0.022	T
MetaSVM	Uncertain	0.067	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		9.0
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.86	P
Vest4		0.69
MVP		0.86
MPC		1.1
ClinPred		0.029	T
GERP RS		4.7
Varity_R		0.48
gMVP		0.94
Mutation Taster		=99/1	polymorphism

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: rs149804567; hg19: chr9-138670290;